Research Methods in Life Sciences Commons^™

Incorporating New Technologies Into Toxicity Testing And Risk Assessment: Moving From 21st Century Vision To A Data-Driven Framework, Russell S. Thomas, Martin A. Philbert, Scott Auerbach, Barbara A. Wetmore, Michael J. Devito, Ila Cote, J. Craig Rowlands, Maurice Whelan, Sean M. Hays, Melvin E. Andersen, M.E. (Bette) Meek, Lawrence W. Reiter, Jason C. Lambert, Harvey J. Clewell Iii, Martin L. Stephens, Q. Jay Zhao, Scott C. Wesselkamper, Lynn Flowers, Edward W. Carney, Tim P. Pastoor, Dan D. Petersen, Carole L. Yauk, Andy Nong

Martin Stephens, PhD

Based on existing data and previous work, a series of studies is proposed as a basis toward a pragmatic early step in transforming toxicity testing. These studies were assembled into a data-driven framework that invokes successive tiers of testing with margin of exposure (MOE) as the primary metric. The first tier of the framework integrates data from high-throughput in vitro assays, in vitro-to-in vivo extrapolation (IVIVE) pharmacokinetic modeling, and exposure modeling. The in vitro assays are used to separate chemicals based on their relative selectivity in interacting with biological targets and identify the concentration at which these interactions …

Beyond The 3rs: Expanding The Use Of Human-Relevant Replacement Methods In Biomedical Research, Kathrin Herrmann, Francesca Pistollato, Martin L. Stephens

Martin Stephens, PhD

This year marks the 60th anniversary of Russell and Burch’s pioneering book, The Principles of Humane Experimental Technique. Their 3Rs framework has helped to inspire humane and scientific progress in experimental technique. However, it is time to update its strategic application. The 21st century has already seen the development of promising, high-tech non-animal models, such as organs-on-a-chip and computational approaches that, in our view, will replace animals as the default option in biomedical experimentation. How fast this transition will take place will depend on the pace at which these new models are optimized to reflect the biology of humans, rather …

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

Martin Stephens, PhD

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, …

Considering Aspects Of The 3rs Principles Within Experimental Animal Biology, Lynne U. Sneddon, Lewis G. Halsey, Nic R. Bury

Lynne Sneddon, PhD

The 3Rs – Replacement, Reduction and Refinement – are embedded into the legislation and guidelines governing the ethics of animal use in experiments. Here, we consider the advantages of adopting key aspects of the 3Rs into experimental biology, represented mainly by the fields of animal behaviour, neurobiology, physiology, toxicology and biomechanics. Replacing protected animals with less sentient forms or species, cells, tissues or computer modelling approaches has been broadly successful. However, many studies investigate specific models that exhibit a particular adaptation, or a species that is a target for conservation, such that their replacement is inappropriate. Regardless of the species …

The Animal Research Controversy: Protest, Process & Public Policy, Andrew N. Rowan, Franklin M. Loew, Joan C. Weer

Andrew N. Rowan, DPhil

The controversy today regarding the use of animals in research appears on the surface to be a strongly polarized struggle between the scientific community and the animal protection movement. However, there is a wide range of opinions and philosophies on both sides. Mistrust between the factions has blossomed while communication has withered. Through the 1960s, 1970s and early 1980s, the animal movement grew in numbers and financial resources, and developed much greater public recognition and political clout. The research community paid relatively little attention to the animal movement for much of this period but, alarmed by several public relations coups …

Alternatives To Laboratory Animals: Definition And Discussion, Andrew N. Rowan

Andrew N. Rowan, DPhil

The origins of the concept of "alternatives" to the use of animals in research may be traced back to the 1800's and the furore about using live animals in surgical and other experiments. Some of the animal protection societies in England were prepared to accept animal experimentation provided it was performed under anesthesia. Even Dr. Marshall Hall, who championed the spread of experimental medicine in 19th century England, considered it necessary to control and prevent unwarranted, inept and cruel experimentation (French, 1975). The concept of alternatives has developed in the 20th century to encompass not only the reduction (prevention) of …

Investigation Of Zebrafish Larvae Behavior As Precursor For Suborbital Flights: Feasibility Study, Pedro Llanos, Kristina Andrijauskaite, Mark Rubinstein, Sherine S.L. Chan

Pedro J. Llanos (www.AstronauticsLlanos.com)

Mapping Molecular Datasets Back To The Brain Regions They Are Extracted From: Remembering The Native Countries Of Hypothalamic Expatriates And Refugees, Arshad M. Khan, Alice H. Grant, Anais Martinez, Gully Apc Burns, Brendan S. Thatcher, Vishwanath T. Anekonda, Benjamin W. Thompson, Zachary S. Roberts, Daniel H. Moralejo, James E. Blevins

Arshad M. Khan, Ph.D.

Chimpanzee Research: An Examination Of Its Contribution To Biomedical Knowledge And Efficacy In Combating Human Diseases, Jarrod Bailey, Jonathan Balcombe, Theodora Capaldo

Jonathan Balcombe, PhD

Research on captive chimpanzees incurs considerable animal welfare, ethical and financial costs. Advocates of such research claim these costs are outweighed by substantial advancements in biomedical knowledge, and that the genetic similarity of chimpanzees to humans enables the former to make critical contributions to preventing, diagnosing and combating human diseases. To assess these claims, we examined the disciplines investigated in 749 studies of captive chimpanzees published from 1995-2004 inclusive, and subjected 95 randomly selected papers to a detailed citation analysis:

49.5% (47/95) of papers had not been cited at the time of this study; 38.5% (34/95) were cited by 116 …

An Examination Of Chimpanzee Use In Human Cancer Research, Jarrod Bailey

Jarrod Bailey, PhD

Advocates of chimpanzee research claim the genetic similarity of humans and chimpanzees make them an indispensable research tool to combat human diseases. Given that cancer is a leading cause of human death worldwide, one might expect that if chimpanzees were needed for, or were productive in, cancer research, then they would have been widely used. This comprehensive literature analysis reveals that chimpanzees have scarcely been used in any form of cancer research, and that chimpanzee tumours are extremely rare and biologically different from human cancers. Often, chimpanzee citations described peripheral use of chimpanzee cells and genetic material in predominantly human …

An Analysis Of The Use Of Dogs In Predicting Human Toxicology And Drug Safety, Jarrod Bailey, Michelle Thew, Michael Balls

Jarrod Bailey, PhD

Dogs remain the main non-rodent species in preclinical drug development. Despite the current dearth of new drug approvals and meagre pipelines, this continues, with little supportive evidence of its value or necessity. To estimate the evidential weight provided by canine data to the probability that a new drug may be toxic to humans, we have calculated Likelihood Ratios (LRs) for an extensive dataset of 2,366 drugs with both animal and human data, including tissue-level effects and Medical Dictionary for Regulatory Activities (MedDRA) Level 1–4 biomedical observations. The resulting LRs show that the absence of toxicity in dogs provides virtually no …

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 …

Non-Human Primates In Neuroscience Research: The Case Against Its Scientific Necessity, Jarrod Bailey, Katy Taylor

Jarrod Bailey, PhD

Public opposition to non-human primate (NHP) experiments is significant, yet those who defend them cite minimal harm to NHPs and substantial human benefit. Here we review these claims of benefit, specifically in neuroscience, and show that: a) there is a default assumption of their human relevance and benefit, rather than robust evidence; b) their human relevance and essential contribution and necessity are wholly overstated; c) the contribution and capacity of non-animal investigative methods are greatly understated; and d) confounding issues, such as species differences and the effects of stress and anaesthesia, are usually overlooked. This is the case in NHP …

Monkey-Based Research On Human Disease: The Implications Of Genetic Differences, Jarrod Bailey

Jarrod Bailey, PhD

Assertions that the use of monkeys to investigate human diseases is valid scientifically are frequently based on a reported 90–93% genetic similarity between the species. Critical analyses of the relevance of monkey studies to human biology, however, indicate that this genetic similarity does not result in sufficient physiological similarity for monkeys to constitute good models for research, and that monkey data do not translate well to progress in clinical practice for humans. Salient examples include the failure of new drugs in clinical trials, the highly different infectivity and pathology of SIV/HIV, and poor extrapolation of research on Alzheimer’s disease, Parkinson’s …

An Assessment Of The Role Of Chimpanzees In Aids Vaccine Research, Jarrod Bailey

Jarrod Bailey, PhD

Prior to Simian Immunodeficiency Virus (SIV)-infected macaques becoming the ‘model of choice’ in the 1990s, chimpanzees were widely used in AIDS vaccine research and testing. Faced with the continued failure to develop an effective human vaccine, some scientists are calling for a return to their widespread use. To assess the past and potential future contribution of chimpanzees to AIDS vaccine development, databases and published literature were systematically searched to compare the results of AIDS vaccine trials in chimpanzees with those of human clinical trials, and to determine whether the chimpanzee trials were predictive of the human response. Protective and/or therapeutic …

Lessons From Chimpanzee-Based Research On Human Disease: The Implications Of Genetic Differences, Jarrod Bailey

Jarrod Bailey, PhD

Assertions that the use of chimpanzees to investigate human diseases is valid scientifically are frequently based on a reported 98–99% genetic similarity between the species. Critical analyses of the relevance of chimpanzee studies to human biology, however, indicate that this genetic similarity does not result in sufficient physiological similarity for the chimpanzee to constitute a good model for research, and furthermore, that chimpanzee data do not translate well to progress in clinical practice for humans. Leading examples include the minimal citations of chimpanzee research that is relevant to human medicine, the highly different pathology of HIV/AIDS and hepatitis C virus …

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 …

Predicting Human Drug Toxicity And Safety Via Animal Tests: Can Any One Species Predict Drug Toxicity In Any Other, And Do Monkeys Help?, Jarrod Bailey, Michelle Thew, Michael Balls

Jarrod Bailey, PhD

Animals are still widely used in drug development and safety tests, despite evidence for their lack of predictive value. In this regard, we recently showed, by producing Likelihood Ratios (LRs) for an extensive data set of over 3,000 drugs with both animal and human data, that the absence of toxicity in animals provides little or virtually no evidential weight that adverse drug reactions will also be absent in humans. While our analyses suggest that the presence of toxicity in one species may sometimes add evidential weight for risk of toxicity in another, the LRs are extremely inconsistent, varying substantially for …

An Analysis Of The Use Of Animal Models In Predicting Human Toxicology And Drug Safety, Jarrod Bailey, Michelle Thew, Michael Balls

Jarrod Bailey, PhD

Animal use continues to be central to preclinical drug development, in spite of a lack of its demonstrable validity. The current nadir of new drug approvals and the drying-up of pipelines may be a direct consequence of this. To estimate the evidential weight given by animal data to the probability that a new drug may be toxic to humans, we have calculated Likelihood Ratios (LRs) for an extensive data set of 2,366 drugs, for which both animal and human data are available, including tissue-level effects and MedDRA Level 1–4 biomedical observations. This was done for three preclinical species (rat, mouse …

Cancerous Contradictions: The Mis-Regulation Of Human Carcinogens Based On Animal Data, Andrew Knight, Jarrod Bailey, Jonathan Balcombe

Jarrod Bailey, PhD

The regulation of human exposures to potential carcinogens constitutes society’s most important use of animal carcinogenicity data. However, for environmental contaminants of greatest U.S. concern, we found that in most cases (58.1%; 93/160) the U.S. Environmental Protection Agency (EPA) considered the animal data inadequate to support a classification of probable human carcinogen or noncarcinogen.

The World Health Organisation’s International Agency for Research on Cancer (IARC) is a leading international authority on carcinogenicity assessments. For chemicals lacking human exposure data (the great majority), IARC classifications of identical chemicals were significantly more conservative than EPA classifications (p

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 …

The Ethical Limits Of Domestication: A Critique Of Henry Heffner’S Arguments, Colin Allen, Marc Bekoff, Lori Gruen

Marc Bekoff, PhD

Henry E. Heffner argues that “animals bred for research are properly viewed as animals who have successfully invaded the laboratory niche, relying heavily on kin selection to perpetuate their genes.” (1999, p. 134). This view of human–animal interactions is the cornerstone of his defense of animal experimentation in two widely-distributed papers (Heffner 1999, 2001). We argue that Heffner’s defense lacks adequate attention to ethical distinctions and principles.

Moving Beyond The Welfare Standard Of Psychological Well-Being For Nonhuman Primates: The Case Of Chimpanzees, John P. Gluck

John P. Gluck, PhD

Since 1985, the US Animal Welfare Act and Public Health Service policy have required that researchers using nonhuman primates in biomedical and behavioral research develop a plan ‘‘for a physical environment adequate to promote the psychological well-being of primates.’’ In pursuing this charge, housing attributes such as social companionship, opportunities to express species-typical behavior, suitable space for expanded locomotor activity, and nonstressful relationships with laboratory personnel are dimensions that have dominated the discussion. Regulators were careful not to direct a specific set of prescriptions (i.e., engineering standards) for the attainment of these goals, but to leave the design of the …

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 …

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.