Frame News 73 Autumn 2014

FRAME NewsPromoting non-animal laboratory methods through better science

GM animal use — ethics and concernsFRAME’s new director

World Congress 2014

New research projects

Fu

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Issue 73, Autumn 2014

www.frame.org.uk

2 | FRAME News 73, Autumn 2014

Contents3. GM Mice –

an ethical discussion

4. FRAME'S NEW WEBSITEs

5. NEW DIRECTOR

6. NINTH WORLD CONGRESS - PRAGUE

8. NEWS IN BRIEF

9. GIFT CATALOGUE

11. NEWS FROM THE FAL

12. ESSAY CONTEST WINNER

13. DOROTHY HEGARTY AWARD

14. CONCERN OVER NEW STATISTICS

15. PESTICIDE TESTING

FRAME News 72, Autumn 2014

Published by:Fund for the Replacement of Animals in Medical Experiments

Russell & Burch House96-98 North Sherwood StreetNottinghamNG1 4EE

Registered charity number 259464www.frame.org.uk

Editor: Anne Jeffery E: [email protected]

Alternatives to Laboratory Animals (ATLA)www.atla.org.uk

Perspectives in Laboratory Animal Science (PiLAS)www.pilas.org.uk

From the Editor Welcome to the latest edition of FRAME News. This is an exciting time for FRAME. Changes last year have culminated in the appointment of a new Scientific Director (See page 5), which marks the start of a period of new possibilities for the charity.

We have also launched a new, up to date version of our website and given the journal ATLA (Alternatives to Laboratory Animals) a new site of its own. It will mean that published papers will be easier to download than with the old system, and the FRAME website can be updated more regularly to keep you in touch with our projects.

Within these pages you will find details of the research FRAME has undertaken in recent months, as well as its views and opinions on developments in the field of biosciences.

A further increase in reported use of genetically modified mice in UK laboratories has caused concern. See pages 3 and 14 for more on that topic.

- Anne Jeffery (FRAME News Editor)

FRAME News 73, Autumn 2014 | 3

gm mice - an ethical discussionThe latest Home Office figures for experiments in UK laboratories showed another increase in the use of genetically modified mice (GMM). FRAME Scientific Officer Kevin Coll discusses the ethics behind the development.

The foundation for life is DNA. It is the blueprint that sets the stage for organisms of all shapes and sizes, from microscopic bacteria, to the giant redwoods of California, to grow and reproduce. Genetic modification is the process of altering the genome of an organism such that they display certain characteristics that make it possible or easier to study a particular function or system.

Beyond the pursuit of ‘better science’, it is imperative to maintain within the ethical boundaries of both modern society and scientific integrity. These have been outlined in national and international laws and directives but universal unwritten rules of ethical conduct also factor greatly when animals are involved in research. This is made difficult in genetics, where new technologies and improved techniques are actively being developed. It requires large numbers of mice, many of whom are ultimately killed, to produce the desired genetically modified strain. The ever changing landscape can prove challenging to preserve ethical standards.

All involved in the use of GMM should consider some important questions:

Are the large numbers of mice used in the generation of specific strains selected for particular genotypes/phenotypes ultimately wasted? It requires dozens, sometimes hundreds, of mice to produce particular strains, and those that do not express the desired trait are killed.

How often, or effectively, are the Three Rs implemented in the process?The Three Rs (Reduction, Refinement, and Replacement) outlined by Russell and Burch state that the utmost effort should be employed to conserve humane practices that subsequently promote better scientific output, while simultaneously maintaining the welfare of the study animal.

What are the underlying implications of genetic modification? Beyond the obvious ‘playing God’ perspective, we must consider what it means to alter the DNA of any organism. In regard to mice, a close evolutionary relative of humans, the debate over limiting our control on life, and our ultimate capacity for governance, is very relevant.

Where does the path lead us and where does it end?GMM are becoming the most widely used tool for drug discovery and biomedical research, so the importance of questioning whether it is going too far is paramount. Millions of mice are used annually as models in areas of research ranging from cancer to depression. To keep up with the demand for more powerful models, new and more questionable techniques are being proposed. Bioscientists must be conscious of the means as well as the ends if the current trajectories in research continue.


FRAME has undertaken a thorough overhaul of its online presence to bring its image up to date and to make its website more appealing, interactive and useful. The changes began with the launch of PiLAS last year.

Although Perspectives in Laboratory Animal Science is published as part of FRAME’s journal ATLA, it also has its own website so that readers can respond directly to the articles by means of an online form.

For some time FRAME’s old website had been looking drab and crowded, and its content has been difficult to navigate, owing to the architecture of the system behind it. Changes in banking procedures meant that readers were unable to buy access to ATLA articles directly, and the website system could not be updated to restore the service. So it was decided to launch a completely new site and to give ATLA its own platform so that it could maintain its identity and branding.

The new ATLA site was launched in spring in time for the first issue of Volume 42. Past issues as far back as 1988 are also available, and all articles more than two years old can be accessed without charge. Readers must register to access full papers, but abstracts are freely available. Anyone wanting to read an article from the last two years can buy access quickly, through the site, and have immediate sight of it. Any bought articles are automatically listed in the reader’s account area for easy access later. It is also still possible to buy an annual subscription to all articles.

The final stage was to launch a completely new FRAME website with information about the charity, its work and its supporters. The new site has sections for industry, for scientists, for the press and for individuals who are interested in the Three Rs (Replacement, Reduction and Refinement) and the work being carried out to develop and promote them.

FRAME’s new Alternatives Timeline has also been included in the new site. The project began last year after we were approached by overseas researchers who had found it difficult to track down details about non-animal methods. Although plenty of information exists, there was no central point providing links to the major developments in Three Rs science.

FRAME’S NEW WEBSITES


FRAME has appointed a new Scientific Director to oversee its research programme at the Nottingham office.

Dr Gerry Kenna is a drug safety scientist with extensive industrial safety assessment experience, including 11 years in the pharmaceutical industry. Prior to that he had a highly successful academic career.

He is recognised nationally and internationally in the field of human adverse drug reactions.

He studied for a BSc in Biochemistry at the University of Leeds and followed that with a PhD in Biochemistry from the National Institute for Medical Research/Imperial College, University of London.

Following that he undertook a research position at the Liver Unit at King’s College Hospital, London, where he investigated the role played by immune reactions in human liver disease. A key focus of his work was drug induced liver injury, particularly the severe damage caused by the volatile anaesthetic halothane.

He also spent time as Visiting Scientist in the Laboratory of Chemical Pharmacology of the National Institutes of Health in Maryland, USA, where he was able to demonstrate the mechanism behind halothane hepatitis. Subsequently he received a Wellcome Trust Advanced Training Fellowship in Toxicology, which enabled him to return to the UK and to join the Department of Pharmacology at St Mary’s Hospital Medical School in London, where he established a research group investigating the role played by metabolic bioactivation and adaptive immune responses in human adverse drug reactions and was appointed Lecturer and then Senior Lecturer in Pharmacology.

Dr Kenna’s industry career began as a Team Leader in Investigative Toxicology at Zeneca/Syngenta Central Toxicology Laboratory, Macclesfield UK and then as a Principal Scientist in Molecular Toxicology and Hepatic Target Organ Strategy Leader at AstraZeneca, Macclesfield.

His work focussed on the development and implementation of improved and mechanistically based drug safety screening and risk assessment strategies. This provided him with insight into the value that can be obtained from appropriate use of scientifically valid in silico and in vitro approaches, which are more predictive of human adverse reactions than animal based methods.

Dr. Kenna has authored or co-authored more than 90 peer reviewed scientific publications and book chapters, is a Fellow of the British Toxicology Society and a Committee member of the International Society for the Study of Xenobiotics.

“I am very excited about the prospect of working with FRAME. It is a successful and respected organisation with a long history of excellent work in the field of alternatives to animal-based research, and I am pleased that I am going to be part of it.”

^ Dr. Gerry Kenna, FRAME Scientific Director.

NEW DIRECTOR


The theme of this year’s World Congress was “Humane Science in the 21st Century”.

A statement issued by Congress Co-chairs Dagmar Jírová and Horst Spielmann said: “The world congress provides an exceptional forum to underline the importance of both the ethical issues of animal experimentation and the approach to the life sciences in the 21st century.

“During the past two decades, responsible reduction in the number of animals used for scientific purposes and development and improvement of 3R-relevant research methods clearly demonstrate the commitment of the scientific community to provide novel science of higher quality. This approach respects not only human ethical principles, but also animal rights and their social and environmental needs.

“Contemporary high quality research is aimed at increasing the public understanding and confidence in the ethical approaches applied in science and its meaning and significance in modern society.”

Among the keynote speakers at the Congress were Michel Goldman, Executive Director of Innovative Medicines Initiative (IMI), Brussels, Belgium, who also delivered the FRAME Annual Lecture two years ago, and Uwe Marx, Founder and Chief Scientific Officer of TissUse, Berlin, Germany, one of the winners of the FRAME Dorothy Hegarty Award 2012.

Among the posters presented at the Congress was one by FRAME Alternatives Laboratory PhD candidate Richard Maclennan. See page 11 for more details.

WORLD CONGRESS ON ALTERNATIVES

The ninth World Congress on Alternatives and Animal Use in the Life Sciences has taken place in Prague, capital of the Czech Republic.

As usual FRAME attended, with staff, Trustees and laboratory post-graduates taking part in a number of events...


Another poster was presented by FRAME Scientific Research Officer Kevin Coll on the rise in use of genetically modified mice (GMM) in current research, and their relevance as a model for human diseases.

AbstractThere has been an overall decrease in the total number of animals used for scientific procedures in the past 40 years. However, there has been a consistent increase in the breeding and use of genetically modified animals, mostly mice, over the same period. Genetically modified mice (GMM) have become a routine model for researchers in a number of fields, yet many uncertainties and inconsistencies remain. Specifically, there is concern over the relative efficacy of GMM as an in vivo model for human disease and drug development.

This work outlines the relative trajectory of GMM in research and questions their validity. Investigation into the scope of the areas of research, the factors related to the rise in numbers, and the varying mechanisms for genetic modification are made, as well as projections for where GMM research may be heading. The advantages and limitations of GMM are contrasted to determine the relevance and applicability of GMM.

Although some GMM models do provide insights into areas of human disease research, the reliance and assumed ability to correlate results wwith humans may be overstated and requires significant further analysis.

Alternatives in toxicology testingFRAME Publications Officer Dr. Rita Seabra attended the 18th International Congress on In Vitro Toxicology, held in Egmond aan Zee, The Netherlands. Here she discusses the event’s aims and outcomes.

The theme of the congress — Making sense of In Vitro methods — was promising, and the scientific programme did not disappoint. Sessions included talks and posters on current research on advanced in vitro models, body-on-a-chip systems, stem cells, molecular biotechnology in toxicology, nanotoxicology, new paradigms in toxicological risk assessment, and regulatory in vitro toxicology. Attendees were given details of research that is taking place worldwide to overcome the need for animal experiments in toxicology. More specifically, several presentations focused on the development and use of cell and tissue cultures to predict human toxicity and metabolism, and provided examples of the use of computational tools. Two very topical study areas — stem cells and nanotoxicology — had their own dedicated sessions.

The meeting was designed to maximise opportunities for interaction between participants, which led to an informal and scientifically stimulating environment. An addition to this year’s congress was a special event, in the form of a debate, on the advantages and limitations of in vitro toxicology for risk assessment. The central question was “Can we get rid of animal experimentation in toxicology within five years?” It was a lively session and, while the timescale was controversial, most of the audience seemed to agree that it would eventually be possible.


Search for validated, non-animal toxicity tests FRAME is taking part in a new research collaboration to find scientific solutions to major conflicts within the regulations governing cosmetics manufacturers and their ingredient suppliers. The project will explore the feasibility of developing replacement tests for acute toxicity that are scientifically relevant and commercially robust, with the aim of having them adopted as OECD (Organisation for Economic Co-operation and Development) test guidelines.

The partnership is led by XCellR8 Ltd, a Cheshire-based company, which provides non-animal testing services for the cosmetics, personal care and household chemical industries. Other partners are cosmetics company Lush, and Inventya Ltd. The project is funded by the NC3Rs and Technology Strategy Board.

FRAME is involved because of its extensive experience working with cosmetics companies and its past participation in the validation of non-animal alternatives. The collaboration will specifically investigate viable solutions to a challenging conflict within cosmetics manufacturing law. On the one hand the EU’s Cosmetics Regulation (EU 1223/2009) prohibits the use of animals in the testing of cosmetic products and their ingredients. On the other hand, suppliers and manufacturers of cosmetics ingredients are bound by the EU’s REACH regulations concerning the registration, evaluation, authorisation and restriction of chemicals. New substances may need to be tested for REACH registration, but they may be prohibited from use in the EU’s cosmetics industry.

Essay competition winner

FRAME’s recent essay competition “What are the alternatives to using animals in laboratories?” attracted some strong entries. The winner, who received a £300 prize, was 17-year-old Emma Bryan, a student at Cheltenham Ladies College.

Emma’s response to her success: “I am extremely happy to have taken part as I really enjoyed writing the essay and am fascinated by alternatives to animal testing. I intend to pursue Veterinary Medicine at university - but I am really interested in pioneering research in all aspects of science, particularly animal-related.

“I have always been opposed to unnecessary use of animals in experimentation, particularly cosmetics, and so this competition really allowed me to express my personal views combined with scientific innovation. Thank you very much for organising this competition - and I really admire the aim of FRAME and the dedicated research that goes on.”

Extracts from Emma’s essay are on page 12 and the full text can be found on the FRAME website at www.frame.org.uk/frame-essay-competition-winner

News in brief


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Development of a dynamic 3D liver model for chronic toxicity testing.

Technological advancements that provide the opportunity to develop better and more reliable models are essential to translational research. At the FRAME Alternatives Laboratory at the University of Nottingham, PhD candidate Richard Maclennan has been working with the Zyoxel LiverChip device to determine its applicability and limitations for chronic toxicity testing. The LiverChip recreates the in vivo (live) environment of the liver, both in terms of physiology and architecture, in an in vitro (laboratory) model.

Small liver samples, including human, can be maintained and tested for upwards of seven days. Future studies will investigate the capacity for the cultures to last as long as 28 days. This system could potentially act as a means to refine chronic liver toxicity testing on humans, reduce the number and size of samples required, and ultimately replace the need for animal models.

In his introduction Richard says:

“Despite the availability of an ever increasing number of bioreactor and 3D culture systems, there is currently no well described or validated method of culturing primary hepatic cells that could be considered the industry standard. There is a pressing need to develop a system that maintains hepatic phenotype over extended periods of time in order to allow chronic pharmaceutical dosing and chemical toxicity testing.

"The Zyoxel LiverChip device is a promising addition to the field which combines three dimensional cell culture with dynamic flow to create a more physiologically relevant system for primary hepatocyte and non-parenchymal cell culture. The combination of the LiverChip device with both rat and subsequently human primary hepatic cells may provide a test-bed for chronic toxicity testing and will also allow a comparison of the effects of compounds which elicit different responses in rodents and humans.”

Richard’s poster was presented at the ninth World Congress on Alternatives and Animal Use in the Life Sciences in Prague.

^ Richard Maclennan with his poster at the recent World Congress on Alternatives in Prague.

The FRAME Alternatives Laboratory


In an age where the whole of the human genome can be mapped, where magnetic resonance imaging can be used to measure brain activity, and where particles can be made to accelerate to close to the speed of light, it seems almost primitive that animals are still used in medical experiments.

There is no doubt that without animal testing our present level of medical research would be nowhere near as sophisticated as it is today, and a huge number of both human and animal lives would have been lost. Nevertheless, I believe that in vivo testing on animals should become a thing of the past, and be succeeded by more advanced, scientific, moralistic methods of testing such as through experimentation with human stem cells and donated human tissue. In this essay I wish to discuss a recent innovation in the field of alternatives to animal testing, the Organ-on-a-Chip. I believe that this pioneering micro-machine has the potential to replace animals in medical testing entirely.

Companies that use animal testing often find it time-consuming, expensive and unreliable, because animals do not always respond to medication in the same way as humans. Although the development of stem cell research could significantly reduce the number of animals involved in experimentation, it would never eliminate testing completely, because animals would still be required to test function in terms of entire organs or systems.

The Organ-on-a-Chip is a surprisingly simple device, which could completely change the nature of medical testing. By creating a physical model of a human organ condensed into a plastic chip the size of a computer memory stick, the effects of small amounts of drugs on human tissues can be mimicked, accurately and efficiently. Developed using micro-fabrication techniques, the chips currently being researched include lung, liver and bone marrow.

Many pharmaceutical companies have become interested in Organ-on-a-Chip technology already, and I believe that this is a promising advance towards the end of testing on animals. Used on a large scale, they would be much more cost-efficient than animal testing. In addition, the micro-devices could be manufactured using bio-printing from 3D computer models, which is an increasingly popular technology and would make production even more efficient.

The Organ-on-a-Chip combines cells of different tissues to form a model that mimics an entire organ, and can replicate its function and movement. It uses human cells, sourced from stem cells, and techniques of micro-fabrication and nano-engineering to construct these highly innovative organ chips. I think the transition from testing on animals to complete reliance on biotechnology will be gradual, however it is a change that needs to be made in order to keep up with the pace of our rapidly developing world, and also not only to improve the welfare of animals, but to improve the success rate of medical drug testing.


the Organ on-a-Chip... A promising alternative to animal testing. An essay by Emma Bryan - Winner of the 2014 FRAME Essay Competition.

Picture Credit: Thanks to Harvard's Wyss Institute


The DOROTHY HEGARTY AWARDThis year’s Dorothy Hegarty Award has been won by Andrea Zaniboni, Augusta Zannoni, Chiara Bernardini, Cristiano Bombardi, Eraldo Seren, Monica Forni and Maria L. Bacci (Department of Veterinary Medical Sciences — DIMEVET, University of Bologna, Bologna, Italy) and Marco De Cecco (Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI, USA).

Their paper, Development of a Vessel Organ Culture System: Characterisation of the Method and Implications for the Reduction of Animal Experiments, appeared in ATLA 41, pp. 259–269.

The Award is presented annually to the authors of the paper published in the previous year’s volume of FRAME’s scientific journal, ATLA, which, in the opinion of the members of the Editorial Board, is likely to make the most significant contribution to the reduction, refinement and/or replacement of animal experimentation.

Each member of the ATLA Editorial Board is entitled to make up to five nominations for the Award, in rank order. As in previous years, a large variety of papers were nominated, reflecting the diversity of the work published in ATLA, and the wide range of interests of the members of the Editorial Board.

Here, the authors have summarised the importance of their paper to the progress of Three Rs:

“Our research group has used the pig as a biomedical preclinical model for many years. However, the use of this species is really complex, especially because it is less standardisable, as compared to the mouse and the rat. Despite this, the pig has a great value in preclinical studies due to its great similarity to humans (e.g. its genome, anatomy, physiology), especially for research on cardiovascular physiopathology.

“The greatest reduction in experimental animal numbers could be achieved by collecting a large amount of preliminary data from in vitro and ex vivo studies, prior to performing a preclinical in vivo study. In view of this, with a grant from Fondazione del Monte di Bologna e Ravenna, our group developed an ex vivo organ culture system of the pig aorta that could overcome some of the limitations of primary cell cultures (i.e. lack of physiological context). With this method, we aimed to study restenosis/neointimal development and formation and associated molecular biology.

“Our model allows researchers to study vascular processes without the sacrifice of experimental animals, because porcine aortas can be recovered at the slaughterhouse or from control animals sacrificed for other experimental purposes. We really believe that our model has contributed to an improvement in the panel of alternative methods available to study vascular physiopathology, according to the Three Rs principles.”


HOME OFFICE STATISTICS RAISE GA CONCERN

“It is important to realise that, even with genetic alteration, a mouse is still a mouse, or a fish is still a fish. They can never provide a fully accurate model for any human disease.”

- FRAME Scientific Programme Manager

A further increase in the use of genetically altered (GA) animals in laboratories flouts EU regulations and is in direct opposition to the UK Government’s pledge to reduce the numbers involved. If the Government is to have any chance of meeting its commitment to reduce the number of animals used in research it must act soon to deal with the escalating levels of GA animal production.

FRAME is deeply concerned that GA animals now seem to be viewed as some sort of alternative technique and that very little discussion is underway to determine how to stop the rise, or whether the techniques are actually the best research method.

“FRAME has always been concerned about the use of GA animals in research for a number of reasons. Although techniques used to produce them are improving, some methods are still inaccurate and create a huge number of animals that do not have the necessary genetic alteration an investigation calls for.”

- FRAME Scientific Programme Manager Michelle Hudson-Shore.

Production and breeding of a GA line is based on complex procedures, and requires a high number of animals, including embryo donors, vasectomised males and foster females. Cross-breeding stages can result in up to three quarters of the offspring having the wrong gene make-up, so hundreds of animals are bred but not used. They are simply killed.

GA mice have become a routine model in a number of fields, in spite of many uncertainties and inconsistencies. FRAME is currently undertaking a review of the use of GA mice an in vivo (live) model for human disease, to monitor the trajectory of their increased use and to investigate their validity.

Following the introduction of the 1986 Animals (Scientific Procedures) Act total animal use in UK laboratories began to fall, but it has risen steadily since a minimum in 2001, and continues to climb.

DogsFRAME is also dismayed to see the continuing use of dogs as a second species in pharmaceutical safety and efficacy studies in spite of a study published last year, that looked at the results of 2,366 published cases of dog-based research, and showed their accurate prediction rates to be little better than chance.

PrimatesThe continued use of non-human primates is disappointing. Although primate use appears to be minimal, accounting for only a very small percentage of procedures in the UK, the highly social nature of monkeys, and their complex behavioural activity, means it is highly likely that they are able to understand what is being done to them and their cage mates.

In addition, given their close similarity to humans, they tend to be used in late-stage testing, and experience more severe pain, suffering and distress, rendering results gained from them even less reliable. Stress causes hormonal changes that affect responses to test drugs. as a result, drugs tested on monkeys in the past have been found to be ineffective or even toxic when used humans. The use of monkeys, and the most recent developments of genetically modified monkeys is questionable at best.

The numbers:Procedures carried out on GA animals: 2012 – 2,433,500 2013 – 2,511,929

Procedures carried out on dogs: 2012 - 4,843 2013 – 4,779


PESTICIDE TESTING

FRAME was recently asked by a household goods manufacturer if it is possible to draw up a single policy statement on animal experimentation that would cover all products from cosmetics to pesticides. Here FRAME Trustee Dr. Richard Clothier considers the implications.

Many international studies have shown that tests on cells are good predictors of toxicity, particularly when new materials or formulations are compared with substances they are designed to replace or improve on. Unlike cosmetics, which are designed to cause no adverse reaction, pesticides are designed to kill, so the questions about unwanted side effects are different.

One concern related to pesticides is their effect on non-target species and the environment. To what level can pesticide testing be replaced by alternative experiments, since their effects are intended to be lethal?

Toxicity to the target species often relies on a metabolic pathway, so in terms of the non-target species the effects of the test substance will depend on differences in metabolism between the target and other species.

Computer based systems already exist that interrogate chemical structures and can identify particular structures that express toxic potential. They can also predict the way a chemical will be metabolised, thus also allowing the products to be screened for their toxicity. By using our knowledge of particular metabolic differences between target and non-target species it is possible to screen for suitable chemicals without even making them, or requiring direct exposure to both target and non-target organisms through experimentation. (This is replacement).

There are a number of in vitro (non-animal) methods available that also examine tissue specific sensitivities so it is possible to select the most likely substances to take forward for further testing. Having knowledge of their likely toxic levels and reactions means that if animal tests are required they can be limited. Once at-risk non-target species are identified they can be tested on a much more limited basis. (This is reduction).

Testing can be designed with increasing dosage from a low level, only until the first signs of a toxic reaction are observed, at which point the test could be stopped. (Since any further increase would be unnecessary because it would probably be fatal). Hence the use of replacement experiments would lead to reduction in animal use and suffering.

NEWS IN BRIEF A new banner (see right) in the lobby of FRAME’s Nottingham office is already attracting attention from passers-by.

FRAME has passed 2,500 likes on Facebook.

There have been recent references to FRAME and its work in numerous journals, newspapers and blogs across Europe.

Several FRAME Corporate Supporters have visited the Nottingham offices and alternatives laboratory to see FRAME’s work in action.

You can now follow FRAME on LinkedIn at: www.linkedin.com/company/2008651

FRAME was featured in A customer leaflet produced by corporate supporter Neal’s Yard.

Professor David Greenaway, the Vice-Chancellor of The University of Nottingham, has been knighted in the Queen’s Birthday Honours. He is a FRAME Patron.

Frame News 73 Autumn 2014

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