Research Methods in Life Sciences Commons^™

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 …

The Scher Report On Non-Human Primate Research — Biased And Deeply Flawed, Jarrod Bailey, Katy Taylor

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The European Commission’s Scientific Committee on Health and Environmental Risks (SCHER) recently issued an Opinion on the need for non-human primate (NHP) use in biomedical research, and the possibilities of replacing NHP use with alternatives, as part of the Directive 86/609/EEC revision process. Here, we summarise our recent complaint to the European Ombudsman about SCHER’s Opinion and the entire consultation process. It is our opinion that the Working Group almost entirely failed to address its remit, and that the Group was unbalanced and contained insufficient expertise. The Opinion presumed the validity of NHP research with inadequate supporting evidence, and ignored …

Interests And Harms In Primate Research, Nathan Nobis

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The article discusses the moral issues on primate research in reference to the moral defenses by Sughrue and colleagues. It states that Sughrue and colleagues have claimed to provide equal examination of the primate stroke research's ethics. It mentions that the promise to straighten out a number of ethical arguments in favor and against primate research was not fulfilled. Several moral arguments are presented in response to Sughrue and colleagues' moral defense for animal experimentation.

The Validity Of Animal Experiments In Medical Research, Gill Langley

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Other animals, such as mice, rats, rabbits, dogs and monkeys, are widely used as surrogates for humans in fundamental medical research. This involves creating disorders in animals by chemical, surgical or genetic means, with the aim of mimicking selected aspects of human illnesses.

It is a truism that any model or surrogate is not identical to the target being modelled. So, in medical research, experiments using animals or cell cultures or even healthy volunteers instead of patients (being the target population with the target illness) will inevitably have limitations, although these will be greater or lesser depending on the model.

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

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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 …

Reviewing Existing Knowledge Prior To Conducting Animal Studies, Andrew Knight

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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 …

Developmental Toxicity Testing: Protecting Future Generations?, Jarrod Bailey

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A recent editorial is discussed, which implied that animal-based developmental and reproductive toxicology tests will continue to be crucial, that the thalidomide disaster could have been prevented by more animal testing, and that tests on juvenile animals would help to protect children (as developing adults) from the adverse effects of pharmaceuticals. It is argued that animal tests in these scientific areas do not provide reliable data that are predictive for human responses and, even if they did, the tests are too expensive and time-consuming for application to the very large number of substances that need to be tested. It is …

The Beginning Of The End For Chimpanzee Experiments?, Andrew Knight

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The advanced sensory, psychological and social abilities of chimpanzees confer upon them a profound ability to suffer when born into unnatural captive environments, or captured from the wild – as many older research chimpanzees once were – and when subsequently subjected to confinement, social disruption, and involuntary participation in potentially harmful biomedical research. Justifications for such research depend primarily on the important contributions advocates claim it has made toward medical advancements. However, a recent large-scale systematic review indicates that invasive chimpanzee experiments rarely provide benefits in excess of their profound animal welfare, bioethical and financial costs. The approval of large …

Systematic Reviews Of Animal Experiments Demonstrate Poor Contributions To Human Healthcare, Andrew Knight

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Widespread reliance on animal models during preclinical research and toxicity testing assumes their reasonable predictivity for human outcomes. However, of 20 published systematic reviews examining human clinical utility located during a comprehensive literature search, animal models demonstrated significant potential to contribute toward clinical interventions in only two cases, one of which was contentious. Included were experiments expected by ethics committees to lead to medical advances, highly-cited experiments published in major journals, and chimpanzee experiments—the species most generally predictive of human outcomes. Seven additional reviews failed to demonstrate utility in reliably predicting human toxicological outcomes such as carcinogenicity and teratogenicity. Results …

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

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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 …

Systematic Reviews Of Animal Experiments Demonstrate Poor Human Clinical And Toxicological Utility, Andrew Knight

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The assumption that animal models are reasonably predictive of human outcomes provides the basis for their widespread use in toxicity testing and in biomedical research aimed at developing cures for human diseases. To investigate the validity of this assumption, the comprehensive Scopus biomedical bibliographic databases were searched for published systematic reviews of the human clinical or toxicological utility of animal experiments. In 20 reviews in which clinical utility was examined, the authors concluded that animal models were either significantly useful in contributing to the development of clinical interventions, or were substantially consistent with clinical outcomes, in only two cases, one …

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

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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 …

Animal Research: A Moral Science, Bernard E. Rollin

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No abstract provided.

The Poor Contribution Of Chimpanzee Experiments To Biomedical Progress, Andrew Knight

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Biomedical research on captive chimpanzees incurs substantial nonhuman animal welfare, ethical, and financial costs that advocates claim result in substantial advancements in biomedical knowledge. However, demonstrating minimal contribution toward the advancement of biomedical knowledge generally, subsequent papers did not cite 49.5% (47/95), of 95 experiments randomly selected from a population of 749 published worldwide between 1995 and 2004. Only 14.7% (14/95) were cited by 27 papers that abstracts indicated described well-developed methods for combating human diseases. However, detailed examination of these medical papers revealed that in vitro studies, human clinical and epidemiological studies, molecular assays and methods, and genomic studies …

A Holistic Approach To Taking Research Animal Suffering Seriously, Martin Stephens, Kathleen Conlee

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It is widely agreed, and often legally required, that distress and pain in research animals should be minimized--for the sake of animal welfare, ethical obligation, and public concern, as well as scientific quality. As testimony to the importance of distress and pain to stakeholders interested in research animals, many countries compile and publish annual statistics documenting overall patterns and trends on distress and pain in research animals.

We argue for a holistic approach to minimizing research animal suffering, with all relevant parties sharing in this responsibility. Researchers, laboratory personnel, oversight committees, and facility administrators are central to day-to-day animal care. …

Overcoming Ideology: Why It Is Necessary To Create A Culture In Which The Ethical Review Of Protocols Can Flourish, Bernard E. Rollin

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My objective in this commentary is to describe and discuss a major threat to the continued thriving of science in our society, which is all the more insidious because it is largely unrecognized by those in the scientific community who are in a position to rectify the problem. Astute people in that community are well aware of many threats to science that include but are not limited to the following: appalling public scientific illiteracy; the unfortunate resurgence of “magic thinking”—reflected in turn in the reappearance of Creationism, which is hostile to evolution—and the billions of dollars spent on evidentially baseless …

Of Mice And Men, Bernard E. Rollin

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No abstract provided.

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

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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 …

Animal Carcinogenicity Studies: Implications For The Reach System, Andrew Knight, Jarrod Bailey, Jonathan Balcombe

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The 2001 European Commission proposal for the Registration, Evaluation and Authorisation of Chemicals (REACH) aims to improve public and environmental health by assessing the toxicity of, and restricting exposure to, potentially toxic chemicals. The greatest benefits are expected to accrue from decreased cancer incidences. Hence the accurate identification of chemical carcinogens must be a top priority for the REACH system. Due to a paucity of human clinical data, the identification of potential human carcinogens has conventionally relied on animal tests. However, our survey of the US Environmental Protection Agency’s (EPA’s) toxic chemicals database revealed that, for a majority of the …

Animal Carcinogenicity Studies: 1. Poor Human Predictivity, Andrew Knight, Jarrod Bailey, Jonathan Balcombe

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The regulation of human exposure to potentially carcinogenic chemicals constitutes society’s most important use of animal carcinogenicity data. Environmental contaminants of greatest concern within the USA are listed in the Environmental Protection Agency’s (EPA’s) Integrated Risk Information System (IRIS) chemicals database. However, of the 160 IRIS chemicals lacking even limited human exposure data but possessing animal data that had received a human carcinogenicity assessment by 1 January 2004, we found that in most cases (58.1%; 93/160), the EPA considered animal carcinogenicity data inadequate to support a classification of probable human carcinogen or non-carcinogen. For the 128 chemicals with human or …

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

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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 …

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

Experimentation Collection

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 …

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

Experimentation Collection

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

Which Drugs Cause Cancer?, Andrew Knight, Jarrod Bailey, Jonathan Balcombe

Experimentation Collection

Animal tests yield misleading results.

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

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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 …

127 Million Non-Human Vertebrates Used Worldwide For Scientific Purposes In 2005, Andrew Knight

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No abstract provided.

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 …

An Evaluation Of The Us High Production Volume (Hpv) Chemical-Testing Programme: A Study In (Ir)Relevance, Redundancy And Retro Thinking, Andrew Nicholson, Jessica Sandler, Troy Seidle

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Under the US Environmental Protection Agency (EPA) High Production Volume (HPV) Challenge Programme, chemical companies have volunteered to conduct screening-level toxicity tests on approximately 2800 widely-used industrial chemicals. Participating companies are committed to providing available toxicity information to the EPA and presenting testing proposals for review by the EPA and posting on the EPA Web site as public information. People for the Ethical Treatment of Animals (PETA) and a coalition of animal protection organisations have reviewed all the test plans submitted by the participating chemical companies for compliance with the original HPV framework, as well as with animal welfare guidelines …