bluuebunny/crossref_metadata_2025 huggingface dataset:
The Effects of Terahertz Radiation on Human Keratinocyte Primary Cultures and Neural Cell Cultures
Authors: Bourne Nicola , Clothier Richard H. , D'Arienzo Marco , Harrison Paul
Published: April 2019

Terahertz (THz) frequencies are found in a previously underexploited region of the radiation spectrum. This non-ionising energy is now being employed in medical imaging, so the possibility of adverse effects on human skin was evaluated. Primary cultures of normal human keratinocytes (NHKs) express adhesion molecules that comprise part of the natural barrier function of the skin. The effects of exogenous agents on this barrier function can be measured. The ND7/23 cell line, which displays the characteristics of sensory neurones, can proliferate in the undifferentiated state, but can be induced to differentiate and develop neurite-like projections. Previous studies with NHK and neural cell cultures produced no evidence of the inability of these cells to differentiate and form a barrier following THz exposure. The cells were exposed to 0.14THz radiation for times varying from 10 minutes to 24 hours. For each 80-nanosecond pulse, the cells were exposed to a peak power of between 24 and 62mW/cm2, i.e. a total energy at peak power of 345J, or 86J at average power over 24 hours. No changes in cell activity occurred, as monitored with the resazurin reduction assay, or with the barrier function of the human corneal cells, as measured with the fluorescein leakage assay. The monitoring of differentiation by using an assay for cornified envelope formation, revealed no adverse effects. Glutathione (GSH) and heat shock protein 70 levels were examined before and after differentiation, to determine the degree of the stress response, with the effects of UVB radiation as a control. UVB induced a stress response, as did heat shock treatment at 43°C, whilst 0.15THz radiation, even after 24 hours of exposure, did not. Repeated exposure to THz radiation at this level, also resulted in no detectable adverse reactions.
The Home Office Statistics for 2007 — Mutant Mice and Fishy Tales
Authors: Hudson Michelle
Published: April 2019

The publication of the Statistics of Scientific Procedures on Living Animals Great Britain 2007 earlier this year, revealed once again that animal experimentation is on the up. This can mainly be attributed to the continuing use of genetically modified mice and an increased interest in investigations and tests involving fish. Here, some of the general trends are described, developments of interest are discussed, and the implications of the statistics are explored.
Reviewing Existing Knowledge Prior to Conducting Animal Studies
Authors: Knight Andrew
Published: April 2019

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 numbers of animal studies for review, serves to minimise bias. Unfortunately, disagreement remained that animal experimental licence applications should reference systematic reviews of existing studies, before approval. The UK Medical Research Council requires that researchers planning human clinical trials must reference such reviews of related previous work. Existing knowledge is thereby fully and appropriately utilised, and redundant experimentation is avoided. However, objections were raised that a similar requirement would interfere with animal experimental licensing, because, to date, there have been very few systematic reviews of animal studies. In fact, the relative dearth of such reviews is a matter of considerable concern, and may partially explain the very poor human success rates of drugs that appear safe and/or efficacious in animal trials. Nevertheless, the disturbing number of human trials which have proceeded concurrently with, or prior to, animal studies, or have continued despite equivocal evidence of efficacy in animals, clearly demonstrate that many researchers fail to conduct adequate prior reviews of existing evidence. Where neither sufficient primary studies, nor systematic reviews of such studies, exist, for citation within a licence application, researchers should be able to provide evidence of this shortcoming, and, concurrently, demonstrate that the available literature and evidence have been adequately reviewed. This should also enable them to clearly demonstrate the need and scientific appropriateness of their proposed study, the validity of its design, and — importantly — that the benefits are reasonably likely to exceed the animal welfare, bioethical and financial costs. Invasive animal studies should never be permitted solely on the basis of less probable, speculative or intangible human benefits, or the mere satisfaction of scientific curiosity.
More is Less: Reducing Animal Use by Raising Awareness of the Principles of Efficient Study Design and Analysis
Authors: Howard Bryan , Hudson Michelle , Preziosi Richard
Published: April 2019

Good experimental design and the appropriate use of statistical tests form the corner stone of high-quality scientific research. This is especially important when the experiments involve the use of laboratory animals, to ensure that their use is appropriate and that the minimum number of animals will be used that will provide data which are sufficiently statistically-sound to meet the objectives of the study. One way to raise awareness of the importance of efficient study design and analysis is to provide training courses. This paper reports the views of participants at two such training schools, with reference to why they felt that attendance was necessary and how effective they felt the experience had been. The implications of the responses are discussed, and considerations for future training events are noted.
Worldwide Trends in the Use of Animals in Research: The Contribution of Genetically-modified Animal Models
Authors: Ormandy Elisabeth H. , Schuppli Catherine A. , Weary Daniel M.
Published: April 2019

The Three Rs — Reduction, Replacement and Refinement — which were first proposed in 1959 by Russell and Burch, have become widely accepted principles in the governance of humane animal research. However, there is substantial variation in the ways in which different countries document the numbers and types of research animals used, making it difficult to determine how effectively the Three Rs are being implemented. Here, we provide the first data illustrating worldwide trends in animal use for research purposes. To document global trends in animal use, we sampled 2691 articles from 24 countries, published between 1983 and 2007, in four scientific journals. We show that the percentage of articles reporting animal use has risen in the past 15 years. The rising popularity of genetic modification methods has contributed to this trend: reported genetically-modified animal use has more than doubled since 1997. We also show that mice are the most commonly-used species for genetic modification, and that, even in 2007, relatively inefficient random integration methods were still widely used to achieve genetic modification. These results illustrate shortcomings in the effort to implement the Three Rs in animal research.
Implementation of the Three Rs in Biomedical Research —Has the Turn of the Century Turned the Tide?
Authors: Obora Shoko , Kurosawa Tsutomu
Published: April 2019

There has been increasing pressure from the public against animal experimentation for testing and research purposes. The Three Rs ( replacement, reduction, and refinement) principle is thought to be a key foundation concept in optimising the welfare of animals used in experiments. This retrospective study attempts to investigate the transition of the Three Rs in biomedical research through a review of articles published in Nature Medicine. We categorised all of the articles published in Nature Medicine from 1998 to 2003, on the basis of the pain and distress of the animals used in the experiments featured in the analysed article. We found there were no large fluctuations in the distribution of these categories over this time period. We also examined each article for the presence of a statement relating to the humane use of laboratory animals, and found that the number of articles which included such a statement dramatically increased in 2002. Over the years studied, there was a decreasing trend in the total number of animal types used for the experiments in the articles. Our results suggest that: a) more encouragement by journal editors might improve the attitude of scientists in terms of animal welfare; and b) the progress of replacement appears to be a more long-term effort in the field of biomedical research.
FRAME and the Validation Process
Authors: Balls Michael , Clothier Richard
Published: April 2019

FRAME's historical involvement in the development of the principles of validation, whereby the reliability and relevance of a procedure are established for a specific purpose, and in the practical application of the process, is summarised, and examples of participation in various validation studies on in vitro tests are reviewed. Emphasis is placed on the need for a parallel invalidation process, and on the role of ATLA as a forum for objective reporting and discussion on all aspects of the validation process.
Hurel™ — an In Vivo-surrogate Assay Platform for Cell-based Studies
Authors: Baxter Gregory T.
Published: April 2019

Accurate prediction of the human response to potential pharmaceuticals is difficult, often unreliable, and invariably expensive. Traditional in vitro cell culture assays are of limited value, because they do not accurately mimic the complex environment to which a drug candidate is subjected within the human body. While in vivo animal studies can account for the complex inter-cellular and inter-tissue effects not observable from in vitro assays, animal studies are expensive, labour intensive, time consuming, and unpopular. In addition, there is considerable concern as to whether animal studies can predict human risk sufficiently precisely, because, first, there is no known mechanistic basis for extrapolation from high to low doses, and second, cross-species extrapolation has frequently been found to be problematic with respect to toxicity and pharmacokinetic characteristics. To address these limitations, an interactive, cell-based microfluidic biochip called a Hurel™ was developed. The Hurel system consists of living cells segregated into interconnected “tissue” or “organ” compartments. The organ compartments are connected by a re-circulating culture medium that acts as a “blood surrogate”. The fluidics are designed so that the primary elements of the circulatory system, and more importantly, the interactions of the organ systems, are accurately mimicked. Drug candidates are exposed to a more-realistic animal or human physiological environment, thus providing a higher and more accurate informational content than can the traditional in vitro assays. By affording dynamic assessment of potential toxicity, metabolism, and bioavailability, the device's capabilities hold the potential to markedly improve the prioritisation of drug leads prior to animal studies.
Drug Discovery and Development Tomorrow — Changing the Mindset
Authors: Coleman Robert A.
Published: April 2019

Today's drug discovery and development paradigm is not working, and something needs to be done about it. There is good reason to believe that a move away from reliance on animal surrogates for human subjects in the Pharma Industry's R&D programmes could provide an important step forward. However, no serious move will be made in that direction until there is some hard evidence that it will be rewarded with improved productivity outcomes. The Safer Medicines Trust are proposing that a study be undertaken, involving a range of drugs that have been approved for human use, but have subsequently proved to have limitations in terms of safety and/or efficacy. The aim is to determine the efficiency of a battery of human-based test methods to identify a compound's safety and efficacy profiles, and to compare this with that of the more traditional, largely animal-based methods that were employed in their original development. Should such an approach prove more reliable, the authorities will be faced with important decisions relating to the role of human biological test data in regulatory submissions, while the Pharma Industry will be faced with the key logistical issue of how to acquire the human biomaterials necessary to make possible the routine application of such test methods.
An Immunologic Model for Rapid Vaccine Assessment — A Clinical Trial in a Test Tube
Authors: Higbee Russell G. , Byers Anthony M. , Dhir Vipra , Drake Donald , Fahlenkamp Heather G. , Gangur Jyoti , Kachurin Anatoly , Kachurina Olga , Leistritz Del , Ma Yifan , Mehta Riyaz , Mishkin Eric , Moser Janice , Mosquera Luis , Nguyen Mike , Parkhill Robert , Pawar Santosh , Poisson Louis , Sanchez-Schmitz Guzman , Schanen Brian , Singh Inderpal , Song Haifeng , Tapia Tenekua , Warren William , Wittman Vaughan
Published: April 2019

While the duration and size of human clinical trials may be difficult to reduce, there are several parameters in pre-clinical vaccine development that may be possible to further optimise. By increasing the accuracy of the models used for pre-clinical vaccine testing, it should be possible to increase the probability that any particular vaccine candidate will be successful in human trials. In addition, an improved model will allow the collection of increasingly more-informative data in pre-clinical tests, thus aiding the rational design and formulation of candidates entered into clinical evaluation. An acceleration and increase in sophistication of pre-clinical vaccine development will thus require the advent of more physiologically-accurate models of the human immune system, coupled with substantial advances in the mechanistic understanding of vaccine efficacy, achieved by using this model. We believe the best viable option available is to use human cells and/or tissues in a functional in vitro model of human physiology. Not only will this more accurately model human diseases, it will also eliminate any ethical, moral and scientific issues involved with use of live humans and animals. An in vitro model, termed “MIMIC” (Modular IMmune In vitro Construct), was designed and developed to reflect the human immune system in a well-based format. The MIMIC® System is a laboratory-based methodology that replicates the human immune system response. It is highly automated, and can be used to simulate a clinical trial for a diverse population, without putting human subjects at risk. The MIMIC System uses the circulating immune cells of individual donors to recapitulate each individual human immune response by maintaining the autonomy of the donor. Thus, an in vitro test system has been created that is functionally equivalent to the donor's own immune system and is designed to respond in a similar manner to the in vivo response.
Use of Virtual Patient Populations for Rescuing Discontinued Drug Candidates and for Reducing the Number of Patients in Clinical Trials
Authors: Kleiman Marina , Sagi Yael , Bloch Naamah , Agur Zvia
Published: April 2019

The decreasing cost-efficiency of drug development threatens to result in a severe shortage of innovative drugs, which may seriously compromise patient healthcare. This risk underlines the urgency to change the paradigm in clinical research. Here, we examine a novel concept of conducting virtual clinical trials for efficiently screening drug candidates, and for evaluating their prospects of being brought to the market successfully. The virtual clinical trials are carried out by using virtual patients (denoted Optimata Virtual Patients — OVPs). The OVP, a set of mathematical algorithms that describe the main pathological and physiological dynamic processes affected by the administered drug, has been shown to accurately predict docetaxel efficacy and safety in individual breast cancer patients. We report a test case in which virtual clinical trials have been conducted by using OVP populations for rescuing a discontinued oncology compound, ISIS-5132 (ISIS Pharmaceuticals Inc.). Our in silico study suggested that ISIS-5132 may be efficacious in combination with another drug, sunitinib malate (Sutent®, Pfizer Inc.), for the treatment of prostate cancer. The recommended combined treatment is predicted to result in a higher five-year Progression-Free Survival than monotherapy with either drug alone.
Monitoring Tissue Drug Levels by Clinical Microdialysis
Authors: Müller Markus
Published: April 2019

The in vivo assessment of drug distribution has long been treated as a “forgotten relative” of pharmacokinetics, mainly due to a lack of appropriate methodology. Research was long restricted to the measurement of drug concentrations from biological specimens that are relatively easy to obtain, or to indirect modelling. However, data obtained by these approaches have resulted in considerable confusion about drug distribution and target site delivery, as their interpretation was flawed by several misconceptions, such as the lack of physiological input to pharmacokinetic models, the erroneous view that a tissue is a uniform matrix, and the notion that the entire drug fraction present in various tissue spaces exerts pharmacological activity. Today, drug distribution to the well defined tissue compartment — “interstitial space fluid”, the biophase for many drugs — can be measured relatively cheaply, minimally invasively, and reproducibly, via microdialysis.
FRAME, the Three Rs and the Russell Archive at the University of Nottingham
Authors: Balls Michael
Published: April 2019

The objectives of the Fund for the Replacement of Animals in Medical Experiments (FRAME) are spelled out, as laid down in the Charity's Trust Deed of 1969, and the support of the Charity's trustees, consultants, patrons and staff in all that has been achieved during its first 40 years, are recognised. The recent establishment of the W.M.S. and Claire Russell Archive at the University of Nottingham is recognised as a further important link between FRAME and the University.
An Investment in the Three Rs Can be Very Profitable
Authors: Curren Rodger
Published: April 2019

The Principles of Humane Experimental Technique by William Russell and Rex Burch provides exceptional value, both to practitioners of alternative methodologies and to bibliophiles who enjoy the pursuit of an out-of-print book. I was stimulated to find an original edition by my first visits to FRAME and its Chairman, Michael Balls. The search continued for several years, until I was able to find an edition suitable for presentation to him. During this hunt, I was able to learn a great deal about the Three Rs of Replacement, Reduction and Refinement, and the programmes that FRAME initiated to educate scientists and the general public about alternative approaches. Very importantly, I was able to use many of FRAME's successful strategies to build up a similar organisation in the United States, the Institute for In Vitro Sciences. The double value of this book is now revealed — not only are its concepts scientifically and ethically valuable, but the price now being charged by secondhand booksellers means a more than ten-fold increase in the value of my investment!
The Dr Hadwen Trust for Humane Research: 39 years of Replacement Science
Authors: Farnaud Sebastien
Published: April 2019

The year 2009 will not be remembered mainly because it is the Chinese year of the ox, but probably, for many, because it is Charles Darwin's bicentenary, the 150th anniversary of the publication of his masterpiece, The Origin of Species, the 50th anniversary of the publication by Russell and Burch of The Principles of Humane Experimental Technique, where they introduced the concept of Three Rs, and also the 40th anniversary of the foundation of the Fund for the Replacement of Animals in Medical Experiments (FRAME). FRAME will always remain our senior, since the Dr Hadwen Trust for Humane Research is only celebrating its 39th anniversary this year! After four decades of learning, challenging, contesting, creating, promoting and advancing the Three Rs concept, the idea of the replacement of the use of animals in research has itself become a science, giving the old sterile debate between pro- and anti-vivisectionists a new dimension. Although scientific progress has been the main reason for such changes, it is important to remember that, without the people and organisations whose aim has been devoted to this cause, these changes might never have happened. Still, as illustrated by the 2008 statistics on animal procedures, many more changes will have to be made, and it is by considering the progress achieved during the last 40 years that we can find the strength and motivation to pursue our goal of scientific research and testing that no longer relies on animal-based techniques.
Depolarising Primate Experimentation: The Good, the Bad and the Determined
Authors: Hudson Michelle
Published: April 2019

Until I began working at FRAME, I was not really aware of the Three Rs or FRAME's work to promote and progress them. It soon became clear to me that it made scientific sense and that it could make a difference to many thousands of laboratory animals. As an alternatives advocate, I regularly experience optimism, frustration and determination. This is illustrated most clearly by the primate research dilemma. Here, I describe the positive and negative experiences I have had whilst working toward the goal of replacing primate experiments, and how these have led me to undertake a multidisciplinary PhD project on primate use in biomedical research. The aim is to examine how research scientists view the opportunities and challenges involved in the use of primates in biomedical science, and to investigate the feasibility of phasing out their use. As a result of the research, I hope to provide a new perspective, to depolarise the debate and bring about a constructive dialogue between all parties as to how and when primate research could be replaced.
The Importance of Anniversaries
Authors: Robinson Vicky
Published: April 2019

This year marks a number of important anniversaries for the Three Rs and those organisations involved in their advancement. These include the 50th anniversary of the publication of Russell and Burch's book, The Principles of Humane Experimental Technique, the 40th anniversary of FRAME, and the 5th anniversary for the UK's National Centre for the 3Rs. These anniversaries provide an important opportunity to reflect on past achievements and future challenges.
FRAME: The Early Days
Authors: Rowan Andrew N.
Published: April 2019

The article reviews the early history of FRAME from the perspective of its first “Scientific Administrator”. The roles of Mrs Hegarty the founder, and other early contributors to FRAME's development are described. In addition, the article discusses FRAME's strategic approach to the subject and how Mrs Hegarty's background influenced the development of that approach.
An Assessment of the Use of Chimpanzees in Hepatitis C Research Past, Present and Future: 1. Validity of the Chimpanzee Model
Authors: Bailey Jarrod
Published: April 2019

The USA is the only significant user of chimpanzees in biomedical research in the world, since many countries have banned or limited the practice due to substantial ethical, economic and scientific concerns. Advocates of chimpanzee use cite hepatitis C research as a major reason for its necessity and continuation, in spite of supporting evidence that is scant and often anecdotal. This paper examines the scientific and ethical issues surrounding chimpanzee hepatitis C research, and concludes that claims of the necessity of chimpanzees in historical and future hepatitis C research are exaggerated and unjustifiable, respectively. The chimpanzee model has several major scientific, ethical, economic and practical caveats. It has made a relatively negligible contribution to knowledge of, and tangible progress against, the hepatitis C virus compared to non-chimpanzee research, and must be considered scientifically redundant, given the array of alternative methods of inquiry now available. The continuation of chimpanzee use in hepatitis C research adversely affects scientific progress, as well as chimpanzees and humans in need of treatment. Unfounded claims of its necessity should not discourage changes in public policy regarding the use of chimpanzees in US laboratories.
A Frame Response to the European Commission Consultation on the Draft Report on Alternative (Non-animal) Methods for Cosmetics Testing: Current Status and Future Prospects — 2010
Authors: Balls Michael , Clothier Richard
Published: April 2019

This response on behalf of FRAME to the European Commission's consultation on the five chapters of the Draft Report on Alternative (Non-animal) Methods for Cosmetics Testing: Current Status and Future Prospects — 2010, is via a Comment in ATLA, rather than via the template supplied by the Commission. This is principally so that a number of general points about cosmetic ingredient testing can be made. It is concluded that the five draft chapters do not provide a credible basis for the Commission's forthcoming report to the European Parliament and the European Council on the five cosmetic ingredient safety issues for which the 7th Amendment to the Cosmetic Directive's ban on animal testing was postponed until 2013. This is mainly because there is insufficient focus in the draft chapters on the specific nature of cosmetic ingredients, their uses, their local effects and metabolism at their sites of application, and, in particular, on whether their possible absorption into the body would be likely to lead to their accumulation in target sites at levels approaching Thresholds of Toxicological Concern. Meanwhile, there continues to be uncertainty about how the provisions of the Cosmetics Directive should be applied, given the requirements of the REACH system and directives concerned with the safety of other chemicals and products.
An Assessment of the Use of Chimpanzees in Hepatitis C Research Past, Present and Future: 2. Alternative Replacement Methods
Authors: Bailey Jarrod
Published: April 2019

The use of chimpanzees in hepatitis C virus (HCV) research was examined in the report associated with this paper ( 1: Validity of the Chimpanzee Model), in which it was concluded that claims of past necessity of chimpanzee use were exaggerated, and that claims of current and future indispensability were unjustifiable. Furthermore, given the serious scientific and ethical issues surrounding chimpanzee experimentation, it was proposed that it must now be considered redundant — particularly in light of the demonstrable contribution of alternative methods to past and current scientific progress, and the future promise that these methods hold. This paper builds on this evidence, by examining the development of alternative approaches to the investigation of HCV, and by reviewing examples of how these methods have contributed, and are continuing to contribute substantially, to progress in this field. It augments the argument against chimpanzee use by demonstrating the comprehensive nature of these methods and the valuable data they deliver. The entire life-cycle of HCV can now be investigated in a human (and much more relevant) context, without recourse to chimpanzee use. This also includes the testing of new therapies and vaccines. Consequently, there is no sound argument against the changes in public policy that propose a move away from chimpanzee use in US laboratories.
Mind the Gap
Authors: Aithal Guruprasad P.
Published: April 2019

The unmet needs of biomedical and clinical research are highlighted by reference to drug-induced liver injury (DILI), non-alcoholic fatty liver disease (NAFLD) and its severe form, non-alcoholic steatohepatitis (NASH). Examples in these areas highlight the major limitations of animal models with respect to predicting, examining and managing these clinically significant forms of liver injury. The way in which these knowledge gaps are being bridged by studies involving the use of human tissues and primary cells are described.
A Human Approach to Drug Development: Opportunities and Limitations
Authors: Coleman Robert A.
Published: April 2019

The pharmaceutical industry is failing in its primary function, with increasing expenditure and decreased output in terms of new medicines brought to market. It cannot carry on as it is, without sliding into a terminal decline. It must, therefore, take some positive steps toward addressing its problems. We do not have to look far to see one very obvious problem, namely, the industry's continuing reliance on nonhuman biology as the basis of its evaluation of potential safety and efficacy. The time has come to focus on the relevant, and to realise that more human-based testing is essential, if the industry is to survive as a source of innovation in drug therapy. This can incorporate earlier clinical testing, in the form of microdosing, and promotion of the development of more-powerful computational approaches based on human information. Fortunately, headway is being made in both approaches. However, a problem remains in the lack of functional evaluation of human tissues, where the lack of commitment, and the inadequacy of the tissue resource itself, are hampering any serious developments. An outline of a collaborative scheme is proposed, that will address this issue, central to which is improved access to research tissues from heart-beating organ donors.
Cell- and Tissue-Based Approaches for Cartilage Repair
Authors: Hardingham Tim
Published: April 2019

Damage and degeneration of articular joints is a major healthcare concern, due to the association of joint disease with ageing, the current strong demographic changes in the proportion of elderly in the population, and the increased incidence of trauma in a sports-active younger population. These joints are biomechanical organs that transmit load between bones in our skeleton, and the articular cartilage forms a load-bearing surface that covers the bone within the joints. All the forces across the joints are thus transmitted through the cartilage, and it therefore makes an important biomechanical contribution to joint function. The cartilage is particularly prone to damage, and has limited capacity for natural repair. Although joint replacement is successful, it is less so in younger patients. For these patients, there is currently great interest in developing cell-based treatments for the biological repair of articular cartilage.
A Three-dimensional In Vitro Model of Breast Cancer: Toward Replacing the Need for Animal Experiments
Authors: Holliday Deborah L.
Published: April 2019

While the events leading to breast cancer development are not fully understood, a pre-invasive lesion, ductal carcinoma in situ (DCIS), is recognised as the main precursor of invasive disease. Understanding how pre-invasive lesions develop into invasive breast cancer is critical, since currently there is no way of predicting which tumours are likely to progress, leading to unnecessary surgical intervention or chemotherapy. With a lack of good animal models able to mimic DCIS progression in a laboratory setting, there has been a shift toward developing in vitro human models which more accurately represent human disease. By manipulating individual cell populations in these models, we can recapitulate the complex cellular interactions involved in disease progression, an essential step in understanding breast cancer behaviour.
Physiologically-based Pharmacokinetic Modelling for the Reduction of Animal Use in the Discovery of Novel Pharmaceuticals
Authors: Thomas Simon
Published: April 2019

The challenges of physiologically-based pharmacokinetic (PBPK) modelling and approaches to replacing the use of animals, in order to determine drug pharmacokinetics, are discussed. Reference is made to the limitations of in vivo animal studies in drug discovery. In particular, the ways in which animal studies contribute to drug attrition during the post-preclinical phase of testing are considered.
The Use of In Vitro Systems to Assess Cancer Mechanisms and the Carcinogenic Potential of Chemicals
Authors: Breheny Damien , Oke Oluwatobiloba , Faux Stephen P.
Published: April 2019

Carcinogenesis is a highly complex, multi-stage process that can occur over a relatively long period before its clinical manifestation. While the sequence in which a cancer cell acquires the necessary traits for tumour formation can vary, there are a number of mechanisms that are common to most, if not all, cancers across the spectrum of possible causes. Many aspects of carcinogenesis can be modelled in vitro. This has led to the development of a number of mechanistically driven, cell-based assays to assess the pro-carcinogenic and anti-carcinogenic potential of chemicals. A review is presented of the current in vitro models that can be used to study carcinogenesis, with examples of cigarette smoke testing in some of these models, in order to illustrate their potential applications. We present an overview of the assays used in regulatory genotoxicity testing, as well as those designed to model other aspects that are considered to be hallmarks of cancer. The latter assays are described with a view to demonstrating the recent advances in these areas, to a point where they should now be considered for inclusion in an overall testing strategy for chemical carcinogens.
Is a Compromise Possible in Russia between Animal Advocates and Researchers who use Animals in Harmful Experiments?
Authors: Loukianov Anatoly S.
Published: April 2019

The current situation relating to the use of laboratory animals in Russia, which is primarily characterised by the complete absence of legislation for their protection, is examined and discussed. This lack of regulation causes well-founded protests by animal protection organisations and a number of reputable politicians. It also has a negative influence on the quality of medical and biological research results that are obtained through the use of experimental animals in Russia. The opinion is expressed that the Russian scientific community should be able to build upon the experience of other countries — in particular, members of the European Union, where there is an effective system of self-control over the ethical and legislative regulation of animal-based research. It is suggested that, in Russia, the basic animal protection principles of the Three Rs should be introduced, when the decision on whether to finance scientific projects involving the use of animals is being made.
The Use of an In Vitro-cultured Porcine Nasal Mucosa Model for the Biocompatibility Assessment of Biodegradable Magnesium
Authors: Schumacher Stephan , Stahl Jessica , Bäumer Wolfgang , Kietzmann Manfred
Published: April 2019

The development of an in vitro-cultured porcine nasal mucosa model is described. The model was subsequently used for the biocompatibility testing of resorbable magnesium-based implants, which are intended for use in the nasal cavity of patients with chronic rhinosinusitis (CRS). Test specimens made from either pure magnesium or titanium were incubated with the mucosal tissue for 48 hours. Afterwards, tissue viability, PGE2, IL-6 and IL-8 release, magnesium ion release, succinate dehydrogenase activity, apoptosis and 14C amino acid incorporation, were determined. The results suggested favourable biocompatibility, even in the case of rapidly-degrading pure magnesium. However, presumed effects on protein synthesis and apoptosis could not be confirmed.
The Tenth Anniversary of the Björn Ekwall Memorial Foundation
Authors: Walum Erik , Tähti Hanna , Kolman Ada
Published: April 2019

The Björn Ekwall Memorial Foundation (BEMF) was initiated by the Scandinavian Society for Cell Toxicology in 2001, to honour the memory of Dr Björn Ekwall (1940–2000) and to establish a prize, the Björn Ekwall Memorial Award. The prize is awarded to scientists who have significantly contributed to the field of cell toxicology, and whose work is contributing toward the replacement of animal experiments by alternative toxicity tests. Over the past 10 years, the Björn Ekwall Memorial Award has been presented annually. Björn Ekwall, an outstanding Swedish cell toxicologist, was one of the pioneers in the development and application of alternative methods to animal tests in toxicology. All his scientific work was devoted to in vitro toxicology, and in particular, to the use of cultured human cells for the screening of toxic chemicals. In the middle of the 1980s, he initiated the international Multicentre Evaluation of In Vitro Cytotoxicity (MEIC) project, to evaluate the usefulness of in vitro tests for the estimation of human acute systemic toxicity. To prove his “basal cytotoxicity concept”, he established the MEMO database, in which data on the acutely toxic human blood concentrations of drugs and chemicals were collated from the literature and from clinical studies. He also initiated another project, Evaluation-Guided Development of In Vitro Toxicity and Toxicokinetic Tests (EDIT). The ideas from the EDIT project, together with those from the MEIC project, became the basis for today's international EU projects, e.g. ACuteTox, Sens-it-iv and ReProTect. In this article, 10 years after the start of the BEMF, the scientific achievements of each of the award winners in the field of in vitro toxicology are presented, together with a brief synopsis of their careers.
A Computer Experiment Model to Investigate the Effects of Drug Dosage in Animals, for Use in Pharmacological Education and Research
Authors: Babanli Ahmed , Gunes Ali , Ozturk Yusuf
Published: April 2019

The ACD-IDEA database, which was originally developed by the authors in 2004, is an ongoing compilation of existing data on the in vivo doses of compounds at which various responses in certain animal species have been observed. It can provide an infrastructure for various research/educational efforts, and creates a synergy for new applications. In this paper, some of these applications are described. Specific interfaces within the database are designed for users who are not computer specialists. Users can search the database to find the answer to a query, or they can design a simple virtual animal experiment. In the second case, the interface is used to undertake a dialogue with the system, in order to test the user's knowledge regarding an experiment under consideration, and to allow the user to glean additional information on better experimental planning. The use of this virtual experimental tool should lead to savings in time, animals, materials, and monetary costs, while the effective learning outcomes of pharmacological experiments are maintained or enhanced.
Lessons from Chimpanzee-based Research on Human Disease: The Implications of Genetic Differences
Authors: Bailey Jarrod
Published: April 2019

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 infection in the two species, the lack of correlation in the efficacy of vaccines and treatments between chimpanzees and humans, and the fact that chimpanzees are not useful for research on human cancer. The major molecular differences underlying these inter-species phenotypic disparities have been revealed by comparative genomics and molecular biology — there are key differences in all aspects of gene expression and protein function, from chromosome and chromatin structure to post-translational modification. The collective effects of these differences are striking, extensive and widespread, and they show that the superficial similarity between human and chimpanzee genetic sequences is of little consequence for biomedical research. The extrapolation of biomedical data from the chimpanzee to the human is therefore highly unreliable, and the use of the chimpanzee must be considered of little value, particularly given the breadth and potential of alternative methods of enquiry that are currently available to science.
Eating Nanomaterials: Cruelty-free and Safe? The EFSA Guidance on Risk Assessment of Nanomaterials in Food and Feed
Authors: Sauer Ursula G.
Published: April 2019

Nanomaterials are increasingly being added to food handling and packaging materials, or directly, to human food and animal feed. To ensure the safety of such engineered nanomaterials (ENMs), in May 2011, the European Food Safety Authority (EFSA) published a guidance document on Risk assessment of the application of nanoscience and nanotechnologies in the food and feed chain. It states that risk assessment should be performed by following a step-wise procedure. Whenever human or animal exposure to nanomaterials is expected, the general hazard characterisation scheme requests information from in vitro genotoxicity, toxicokinetic and repeated dose 90-day oral toxicity studies in rodents. Numerous prevailing uncertainties with regard to nanomaterial characterisation and their hazard and risk assessment are addressed in the guidance document. This article discusses the impact of these knowledge gaps on meeting the goal of ensuring human safety. The EFSA's guidance on the risk assessment of ENMs in food and animal feed is taken as an example for discussion, from the point of view of animal welfare, on what level of uncertainty should be considered acceptable for human safety assessment of products with non-medical applications, and whether animal testing should be considered ethically acceptable for such products.
The Perception of Students on the Use of Animals in Higher Education at the Federal University of Paraná, Southern Brazil
Authors: Deguchi Bernardo G.F. , Molento Carla F.M. , de Souza Carlos E.P.
Published: April 2019

The use of animals in education and research is a controversial issue that involves ethical considerations. In Brazil, Act 11,794, which was approved in 2008, established the National Council on the Control of Animal Experimentation (CONCEA) and a database of institutions that use animals for research and education (CIUCA). This legislation also set out the regulations for the use of animals. In this study, we have evaluated the ethical issues involved in the use of animals for educational purposes at the Federal University of Paraná, through a qualitative–quantitative analysis that relied on written questionnaires. Our objective was to find out the opinions of students and staff from different academic fields, and at different stages in their professional development, on the use of animals for educational purposes. The study involved 101 students and 20 lecturers (i.e. tenure-track professors and all those who teach the students) in Biology, Pharmacology, Medicine and Veterinary Medicine. Approximately half of the students (45.5%) did not know the legislation that regulates the use of animals in education, and most of the lecturers believed that learning goals could not be achieved with alternative methods. Only 38.9% of the lecturers and 31.9% of the students trusted the usefulness of alternative methods. Furthermore, recent graduates were as unaware of the legislation, as were students in the first two years of their university courses. These results suggest that it is necessary to considerably expand the discussion on alternatives to animal use in the academic environment.
The Comparability of In Vitro and Ex Vivo Studies on the Percutaneous Permeation of Topical Formulations Containing Ibuprofen
Authors: Stahl Jessica , Blume Bettina , Bienas Silvia , Kietzmann Manfred
Published: April 2019

In order to avoid in vivo experiments and to gain information about the suitability of surrogates for skin replacement, Franz-type diffusion cell experiments were conducted by using three ibuprofen-containing formulations (cream, gel and microgel) on bovine split-skin samples and cellophane membranes. Moreover, ex vivo examinations were performed on the isolated perfused bovine udder, to study the comparability of in vitro and ex vivo experimental set-ups. Depending on the formulation, noticeable differences in the permeation of Ibuprofen occurred in vitro (udder skin) and ex vivo (isolated perfused bovine udder), but not in the cellophane membrane. The rates of ibuprofen permeability (cream > gel > microgel) and adsorption into the skin (gel > microgel > cream) varied with the formulation, and were probably caused by differences in the ingredients. Furthermore, different storage conditions and seasonal variation in the collection of the skin samples probably led to differences in the amounts of ibuprofen adsorption apparent in the isolated bovine udder and udder skin. In vitro diffusion experiments should be preferred to experiments on isolated organs with regard to the costs involved, the throughput, and the intensity of labour required, unless metabolism of the drug in the skin, or cell–cell interactions are of particular interest.
The Forthcoming Launch of Perspectives in Laboratory Animal Science (PiLAS)
Authors: Balls Michael , Trigwell Susan
Published: April 2019

“Scientific knowledge changes perspective. And perspective changes everything…” (James McConnachie, 2012)
Working with Animals in Research
Authors: Cruden Joanna
Published: April 2019

The duties of a Named Animal Care and Welfare Officer include delivering first-class animal care and educating future scientists