Deutsche Forschungsgemeinschaft Animal Experiments in Research Imprint

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Editorial Office: Cornelia Exner (responsible) Hans-Joachim Bode Karin Blumer Christian Giese The German Library – CIP Standard Cataloguing Layout: Regina Fischer Animal Experiments in Research Eds. Senate Commission on Animal Protection and Experimentation, Printed by: Deutsche Forschungsgemeinschaft – Bonn: Lemmens Medien GmbH, 2007 Courir-Media GmbH, Bonn ISBN 978-3-932306-87-7 Production: Lemmens Medien GmbH, Bonn ISBN 978-3-932306-87-7 All Rights Reserved Deutsche Forschungsgemeinschaft Animal Experiments in Research

Issued by the Senate Commission on Animal Protection and Experi- mentation with the assistance of Cornelia Exner (responsible), Hans-Joachim Bode, Karin Blumer and Christian Giese Contents

Preface 3

Animal experiments: definition and numbers 4 Nematodes, fruit flies, mice 5 What is an animal experiment and which animals are used? 6 Animal experiments in numbers 7

Animal experiments in practice: areas in which experimental animals are used 8 Basic research 9 Increase in medical knowledge Focal points in biomedical research 14 Transplantation medicine 15 Cell and tissue substitutes in man 15 Stem cell research 16 Genome research, animals with mutated genes, transgenic animals 17 Transferability of the results of animal experiments to man 18 Veterinary research 19

Animal experiments & Animal protection: An ethical balance 20 Is it possible to dispense with animal experiments? 21 Are there alternatives to animal experiments? Limitations to alternative methods 23 The three Rs 24 Acceptance of animal experiments 24 Development of the concept of animal protection in Germany 26 Ethical aspects of animal experiments and the solidarity principle 27

Animal experiments in Germany: From application to performance 30 European regulations on animal experiments 31 Animal experiments with the precondition of approval 32 Interpretation of the Animal Welfare Act for the area of animal experiments 32 What is the legal definition of "essential"? 33 What is the legal definition of "ethically defensible"? 33 Approval procedures 34 Performance of animal experiments 34 Monitoring of the experiment 35 Stress during animal experiments 36 Who is allowed to perform animal experiments? 37 How is the training performed? 37

Summary 38

 Preface

he Deutsche Forschungsgemeinschaft are closely connected. The financial support (German Research Foundation, DFG) for the latter approaches in basic research has Tand the Max Planck Society (MPG) rec- long been greater than for actual animal ex- ognise the enormous ethical responsibility periments. Replacement and complementary which is linked to basic biological and medi- methods are used to acquire detailed knowl- cal research. When supporting and performing edge on cellular structures and processes, experimental research with animals, this is the which are then validated in animal experi- aspect on which they concentrate particularly. ments. Only with this combination is it possi- Animal protection is an important social bly to recognise and understand the processes issue in many European countries. A high de- which occur in nature in the living organism gree of animal protection has been established and finally - with the necessary modifications in Germany. The DFG and MPG are aware - in the human body. We consider that causal that experimental animals must be kept ap- research is impossible without animal experi- propriately to the species and be dealt with ments. sensitively, and that this is not only an ethical This study is presented by the DFG Sen- necessity, but also a precondition for the qual- ate Committee for Animal Experiments in Re- ity of experimental research on animals. Ac- search. It is intended to fulfil the wish for up- cordingly, they have always made every effort to-date and intelligible information on animal to improve the conditions under which exper- experiments in research, as expressed in an imental animals are held and to ensure that opinion survey among different social groups they are treated as carefully as possible. An- and experts. We hope that readers interested imal experiments and replacement and com- in research and animal protection will profit plementary methods for animal experiments from reading it.3

Professor Dr.-Ing. Matthias Kleiner Professor Dr. Peter Gruss President of the German Research Foundation President of the Max Planck Society

 Animal Experiments: Definition and Numbers Animal Experiments: Definition and Numbers Nematodes, fruit flies, mice

n 2000, a report caused a sensation through- is that the results of animal experiments can- out the world. Scientists had succeeded in not be transferred to man and that animals Ilargely decoding the human genome. The are made to suffer just to satisfy scientific cu- analysis of the hereditary information (DNA) riosity. Some of the original experiments on of complex animals - such as humans, the fruit animals now really do appear cruel - but the fly Drosophila melanogaster, the rat and the same applies to surgery on man in the same mouse – is one of the most important scien- period. The main reason is that the operative tific achievements of recent years. However, techniques and possibilities for anaesthesia major progress has been made in other areas were inadequate. The discovery of anaesthe- of the biosciences, including new knowledge sia was a blessing for both animals and man about the structure of the ribosomes - the pro- and is now routine in animal experiments. tein factories in body cells - and the possibil- Even in the 19th century, criticism of an- ities of using stem cells in treating diseases. imal experiments led to new laws for the use New knowledge of this sort has often helped of animals in research. These have been con- to improve our medical care and nutrition and tinuously improved and all European coun- has helped to ensure increases in life expect- tries now possess detailed legal regulations ancy and improvements in the quality of life. for the performance of animal experiments. Progress in the biosciences would be in- The German Animal Welfare Act is one of conceivable without the use of animal ex- the most restrictive in the world. This ensures periments. It has only been possible to un- that animal experiments are only performed derstand processes in the organism with the to an extent which is accepted by society and help of animal experiments. This includes the is subject to official monitoring. Before an an- function of the sense organs and of the nerv- imal experiment for biomedical research is ous, hormonal and immune systems. Animal performed in Germany, there is a hearing in experiments will also be necessary in future, an Animal Protection Committee, with mem- for example in understanding the functions of bers including scientific experts and repre- genes, as the significance of individual genes sentatives of societies for animal protection. for the total organism can only be established As part of a balanced consideration of legally in the intact living organism. protected values, this committee evaluates Animal experiments have been used for not only the scientific necessity of an animal centuries to study physiological processes experiment, but, in particular, its ethical de- and to develop new medical methods. How- fensibility. It is often difficult to reach this de- ever, there have been opponents of these cision and there may be differences of opin- experiments for just as long. Then as now, ion. Legally prescribed animal experiments they accuse scientists of giving humans pri- include checking the safety and efficacy of ority over animals. Another point of criticism drugs for man. In such cases, the necessity of

 Animal Experiments: Definition and Numbers

human protection is reason enough to make it the three Rs and are aimed at Reducing and Re- unnecessary to justify each individual exper- fining animal experiments and their Replacement iment separately. To ensure the high bioethi- with alternative or complementary methods. cal standard in animal experimental research These principles are also implicitly laid down throughout Europe, the European Science in the German Animal Welfare Act, with the Foundation (ESF) – an association of organi- addition of the aspect of ethical evaluation. sations supporting research – has developed In spite of these legal regulations, may peo- a position paper for dealing with experimen- ple retain their reservations about animal ex- tal animals. This emphasises the significance periments and consider that the legal regula- of three important principles which must be tions are too weak.3 considered in research. These are known as

What is an animal experiment and which animals are used?

he 1998 version of the German Animal ity that they could be linked to pain, suffering Welfare Act defines animal experiments or damage. The conditions under which these Tas, "Experimental procedures or treat- animals are kept and cared for are also offi- ments of animals, if these may be linked to cially monitored. pain, suffering or damage to these animals, Animal experiments requiring notifica- or on the hereditary material, if these may tion include legally prescribed animal exper- Proportion of Species 2004 be linked to pain, suffering or damage to the iments (for example, from the laws on drugs (in per cent) animals with modified hereditary material or and chemicals), experiments to test vaccines the animals which bear these "(§ 7). Animal during the approval procedures, the removal 55.9 Mice experiments are only permitted in Germany of organs and experiments for training or for the following four purposes: research to postgraduate training (e.g. of medical or bi- maintain health in man or animals, detec- ology students). In contrast, in public discus- 0.91 Farm Animals 0.23 Dogs tion of effects endangering the environment, sions, the term "animal experiment" is mostly 0.09 Nin Human checking the safety of drugs or chemicals and used more broadly and includes every use of Primates Rats basic research. animals for scientific or medical purposes. 0.03 Cats 23.7 The Animal Welfare Act distinguishes The Council of Europe guideline defines ani- between animal experiments requiring ap- mal experiments more broadly than the Ger- proval and those requiring only notification. man Animal Welfare Act. This considers all The legal regulations apply in principle to areas in which animals are used for experi- all animal species, including worms, insects ments or other scientific purposes. Animal ex- Fish Rabbits Birds Other Rodents 6.5 Animals Other and cold blooded and warm blooded verte- periments are mostly performed on rodents, 4.9 2.7 3.9 2.9 brates. Experiments on vertebrates are sub- particularly mice and rats. Somewhat fewer

Source: ject to especially strict conditions and require experiments are performed on guinea pigs. BMVEL Animal Protection Report 2005 approval in principle, if there is the possibil- Large great apes – such as chimpanzees and

 Animal Experiments: Definition and Numbers bonobos – have not been used in animal ex- loris and others) is below 0.1% of all experi- periments in Germany since 1992. The num- mental animals and has remained about con- bers of other types of primates (mandrills and stant in recent years.3 new-world monkeys) and of lemurs (galagos,

Animal experiments in numbers

n 2005, 2.41 million experimental ani- gan removal which caused this increase in mals were used in Germany. The number the numbers of experimental animals. Iof experimental animals fell continuously Many of the experiments performed still from 1991 to 1997, with an overall reduction serve consumer protection. Many of the ex- of up to 40%. The numbers have increased perimental animals used in Germany in 2005 again since 1998; this is mainly due to the too were for safety testing, quality controls increased use of so-called transgenic mice. or toxicology testing. This includes testing These animals are used in biomedical re- of drug tolerability and testing of the envi- search to identify the genetic causes of dis- ronmental risk from substances (for exam- eases and to develop new therapeutic pro- ple, testing of industrial waste water). Many cedures. Although the number of animal of these animal experiments are legally pre- experiments had declined in previous years, scribed and are the precondition for the ap- there has been an increase in the number of proval of drugs or of other substances with experimental animals since January 2000. which humans come into contact. Similar fig- Proportion of Species 2005 This is mostly due to increases in the numbers ures have been recorded in other European (in per cent) of mice and rabbits and is linked to changes countries, for example Great Britain. in the method of counting in the new order The number of experimental animals on reporting numbers of experimental ani- used in research makes up about 0.5% of all 59.4 Mice mals. Whereas the old reporting order only animals killed annually in Germany. 99.5% of counted animals which counted as experi- the animals are killed for other purposes, par- 0.99 Farm Animals mental animals in accordance with § 7 of the ticularly for human food. Thus more than 48 0.2 Dogs Animal Welfare Act, the new order also in- million pigs, more than 3.4 million cows, 2.1 0.08 Nin Human cludes those animals used for scientific train- million sheep and goats (Federal Statistical Primates ing, the isolation of vaccines and sera for vac- Office and Federal Ministry of Food, Agricul- Rats 0.04 Cats 23.7 cination, for organ removal or for cell culture. ture and Consumer Protection). The number About a third of the recorded animals were of chickens killed is about 476 million, which used for purposes which did not have to be is much higher still. Aside from food, animals reported according to the old legislation. Ac- are also killed in large numbers during pest Other Rodents Other Animals Other Fish Rabbits cordingly, the current numbers of experimen- control and by hunters and anglers. The an- Birds 2.4 1.9 tal animals are not comparable with the fig- nual average is that about 250,000 wild pigs 4.1 4.2 4.0 ures from previous years. It was mainly the and one million roe deer are killed (German Source: inclusion of animals killed painlessly for or- Association for the Protection of the Hunt).3 BMVEL Animal Protection Report 2006

 Animal Experiments in Practice: Areas in which experimental animals are used Animal Experiments in Practice: Areas in which experimental animals are used Basic Research

he aim of basic research is to acquire Many results in basic research are found new knowledge which can form the ba- by using cell cultures. In cancer research, Tsis for applied research. Basic medical these studies are intended to aid the under- or biological research is not intended for any standing of the cell biological principles of direct medical application, but develops the the formation of cancerous cells. Parallel to scientific foundation on which all subsequent this, the development of the tumour is studied research is based. Basic medical research in the living animal, in so-called animal mod- uses laboratory animals to identify the pre- els like the mouse. Once the mechanisms Running for research conditions for research which is directly re- of tumour formation and growth are more The times when a laboratory lated to the patient. The resulting knowledge closely understood, useful research on new mouse climbs into a running facilitates the understanding of living proc- therapeutic approaches will be possible. wheel to get some exercise esses and how they may be disturbed. Al- Animal experiments are also necessary though the implementation of the results of for research into infectious diseases. Here it are not distributed randomly basic research cannot be planned and its di- is a question of identifying the infection throughout the day, but follow rect benefits cannot be predicted in the short routes and the mechanism of the immune a circadian rhythm, which is term, biomedical research without it is totally response. Basic research has an established evidently genetically influenced. inconceivable. role in bacteriology, virology, parasitology, With the help of a computer, the running wheel activity is measured and evaluated.

Current examples of medical research

} Improved diagnosis and treatment of cancer } Improvement of transplantation procedures } Improved diagnosis and treatment of cardiovascular } Development of artificial organs to replace loss diseases of organ function (biomaterials) } Improved treatment of metabolic diseases, such as } Further development of neuroprostheses for diabetes mellitus paraplegic patients } New treatments for autoimmune diseases, such as } Improvement in non-invasive diagnosis (e.g. com­ rheumatism and multiple sclerosis (MS) puter tomography, CT) } Improved allergy treatment } Research on the potential of stem cells as new therapeutic approach } Development of treatments and vaccines for AIDS } Development of new approaches for somatic gene

} Diagnosis and specific treatment of neurological therapy for hereditary immune deficiencies diseases such as Parkinson's and Alzheimer's diseases

 Animal Experiments in Practice: Areas in which experimental animals are used immunology and tropical medicine. Knowl- tact organisms. This also applies to compara- edge of the interaction between viruses and tive studies of the function of the nervous sys- their host cells allows specific treatment of tem, the cardiovascular system and the mode viral diseases, such as flu, herpes infections of action of hormones. or smallpox, and preventive measures. For There are also very dynamic develop- example, this knowledge has been imple- ments in the areas of genomic and stem cell mented in the area of protective vaccina- research. It is hoped that stem cell research tion. Animal experiments are necessary, as may lead to new therapeutic approaches for the complex interrelationships in the disease the treatment of neurological diseases, such process can only be investigated in live, in- as Parkinson's disease, or of heart attacks. 3

Examples of the use of animals is research

Rat, Mouse Rabbit Cancer research Vaccine development Metabolic diseases Tests of drug activity Tests of drug activity Genome research

Pig Cow, Horse Transplantation surgery Vaccine development Osteosynthesis and isolation Emergency surgery Veterinary research Diabetes research Cardiovascular diseases Osteoporosis research Veterinary research

Dog Cat Cardiovascular research Heart surgery Heart surgery Neurophysiological studies Bone marrow transplantation Development of hearing aids Osteosynthesis Research on cat leukosis Diabetes research Veterinary research Veterinary research

10 Animal Experiments in Practice: Areas in which experimental animals are used Increase in medical knowledge

edical progress is inseparably linked include the development of antisera to diph- to basic research and the use of ani- theria (guinea pigs), vaccines against yel- Mmal experiments. An excellent exam- low fever and polio (mouse and monkey) and ple of the medical application of knowledge studies on the pathogenesis of tuberculosis from research with animal experiments is the (sheep and cow), typhus (mouse, rat and mon- development of methods for treating diabe- key) and malaria (dove). This was pioneering tes mellitus. In the 1920s, insulin was identi- progress in medicine. Animal models are still fied as a hormone which regulates blood sugar used today in medical research. For exam- concentration. Studies on dogs and rabbits led ple, the 1996 Nobel Prize was awarded for the to this discovery and helped to understand the studies of Rolf Zinkernagel (Switzerland) and action of insulin on blood sugar concentrations Peter Doherty (Australia) on the organism's and to develop new therapies. In 1923, the Ca- immune response to virus-infected cells. Some nadian scientists Frederick Banting and J.J.R. of these advances were based on experiments McLeod were awarded the Nobel Prize for the with mice. The American Stanley Prusiner discovery of insulin. Dogs and rabbits were used experiments on hamsters and mice to Learning and later replaced to a large extent in physiological identify prions as the trigger of diseases lead- memory training research by rats and mice. The rapid reproduc- ing to neuronal degeneration. Prusiner was Cognitive processes – the tion of these species permitted specific breed- awarded the 1997 Nobel Prize for this work. ing for individual clinical presentations. These Animal experiments have led to the de- processes of learning, memory include the so-called "diabetes mouse", with velopment of new surgical techniques and and perception – are impaired raised blood sugar values, and the "Zucker to the refinement of operating methods. The in many psychic diseases. rat", which suffered from severe obesity. first experiments on tissue transplantation These disturbances serve to Immunology is another important research were performed in the mouse at the start of impair the patient's quality of area which could not dispense with the use of the 20th century. These days, animal mod- life. Animal models are used animals. Themes studied include protection els are used for kidney transplantation, bone from pathogens and rejection of transplants marrow transfer and heart surgery, to develop to investigate new therapeutic after an organ transplant. There are numer- new methods for the cure or alleviation of or- approaches and their con- ous examples of the usefulness of animal ex- ganic diseases in man. Pigs are usually used, ­sequences for memory per­ periments in the development of vaccine sera but also dogs and sheep.3 formance or learning behaviour and the study of the course of diseases. These

11 Animal Experiments in Practice: Areas in which experimental animals are used Animal experiments: Increases in medical knowledge

1900 } Treatment of vitamin deficiencies, such as rickets } Electrocardiography in the frog (ECG) and heart catheter } Passive immunisation against tetanus and diphtheria (rabbit, mouse, horse as serum donor, guinea pig) } First transplantation experiments in the mouse

1920 } Discovery of thyroid hormones, leading to the possibility of treating poor thyroid function } Discovery of blood sugar regulation by insulin (first experiments in dogs)

1930 } Therapeutic benefit of sulphonamides, a group of synthetically produced drugs used for syphilis } Vaccination against tetanus } Development of blood clotting factors, modern anaesthetics and neuromuscular inhibitors

1940 } Therapy of rheumatoid arthritis and whooping cough } Discovery of the therapeutic benefit of various antibiotics, including penicillin and streptomycin } Discovery of the rhesus factor (rabbits and rhesus monkeys) } Treatment of leprosy } Factors to evaluate the tissue tolerance of transplantations

1950 } Oral vaccination against polio } Discovery of the first chemotherapies for cancer } Cardiac pacemakers and open heart surgery

1960 } Vaccination against German measles } Bypass operations on the heart } Therapeutic benefit of cortisone } Development of radioimmunoassays (RIA) for the detection of tiny quantities of antibodies, hormones and other substances in the body } Discovery of antihypertensive drugs

12 Animal Experiments in Practice: Areas in which experimental animals are used Animal experiments: Increases in medical knowledge

1970 } Vaccination against measles, extinction of smallpox } Treatment of disturbances in the perfusion of coronary arteries } Heart transplantation } Development of new non-addictive analgesics } Discovery of oncogenesis (=origination and development of malignant tumours) } Laser therapy for retinal detachment } First antiviral drugs } Development of monoclonal antibodies (=antibodies from the descendants of genetically identical cells) (mouse) } Improvements in intensive medicine

1980 } Organ transplantation (dog, pig) } Use of cyclosporine, an antibiotic to reduce transplant rejection } Implantation of artificial hearts } Vaccines against hepatitis B } Azidothymidine (AZT) for the treatment of AIDS } Treatment of deafness with cochlear implants (=inner ear implants) (cats) } Drugs to lower cholesterol } Discovery of genes to suppress tumours } Studies on the formation of cancer metastases } Treatment of leukaemia in children } Disintegration of kidney stones by ultrasound } Diagnosis and treatment of borelliosis, a bacterial disease transmitted by ticks

1990 } Improvements in operative techniques in minimally invasive surgery (endoscopy) to minimise stress on the patient and to accelerate recovery } New diagnostic and therapeutic approaches in the treatment of breast cancer } Separation of hereditary predisposition and environmental effects in the initiation of breast cancer

2000 } Decoding of the genome for the fruit fly, mouse, rat and man

13 Animal Experiments in Practice: Areas in which experimental animals are used

Focal points in biomedical research

s a consequence of improved med- sion tomography (PET) and computer tom- ical care in western countries, hu- ography (CT) and do not require any sort of Aman life expectancy has increased operation, so that they are less disturbing for and neonatal mortality has decreased. In the patient. Together with the development spite of medical progress, many diseases can of new contrast media, these open up new Causes of 58 million deaths in the world only be treated sympto- diagnostic possibilities. The American Allan matically, as their origin M. Cormack and the Englishman Godfrey N. cancer has not yet been ade- Hounsfield were awarded the Nobel Prize in cardiovascular quately researched. So- 1979 for the development of computer tomog- diseases 13 % ciety therefore still has raphy, for which they used the pig and other great hopes of progress animals as model organisms. These highly other in medical care. sensitive diagnostic procedures are also used 10 % 29 % In many diseases, to treat domestic animals in veterinary med- successful treatment de- icine. Experience gained in human medicine respiratory and gastrointestinal 10 % pends on diagnosis in with ultrasound diagnosis, X-rays and com- diseases good time. This is why puter tomography is also exploited in modern 9 % 29 % much medical research veterinary medicine. is concentrating on im- In chronic diseases, such as diabetes mel- accidents infectious proving diagnostic me­ litus, rheumatism and multiple sclerosis (MS), diseases thods. Non-invasive di- but also in allergies, the objective is to allevi-

Source: agnostic techniques ate the stressful symptoms and to prolong life WHO, 2001 include positron emis- expectancy.3

Current focal points in basic research

4 Cell biological and molecular genetic principles 4Research on stem cells to develop methods 4 Function and interactions of genes (genome for the origin and growth of cancer cells to treat neurological diseases (such as research) 4 Function of viruses and their interaction with Parkinson’s disease) or to replace tissues 4 Origin and development of organs (for example, myocardial infarction) host cells – specific treatment of viral infections 4 Control of gene expression to clarify the function 4 Function of the nervous system and of the 4 Research on tropical and subtropical diseases, and functional disturbances of the cardiovascular hormones such as malaria and haemorrhagic fever system, the reproductive organs, the hormone 4 Function of the heart and of the cardiovascular 4 Gene transfer to treat hereditary diseases system and others system, to increase knowledge of cardiovascular 4 Neurobiologische Forschung zum besseren 4 Knockout mice and transgenic mice strains as diseases Verständnis der Gehirnfunktionen animals models for human clinical presentations 4Immunobiology and parasitology 4 Neurobiological research to increase understand- (e.g. deafness, metabolic disturbances) ing of brain functions

14 Animal Experiments in Practice: Areas in which experimental animals are used

Transplantation medicine

bout 3,500 organ transplantations are tation of organs from one animal species to performed each year in Germany. For another, or from an animal to man. This has Athe recipients of the organs, this pro- a special role in transplantation research. cedure is either life saving, or leads to a great The studies aim at finding species with or- improvement in the quality of life. The oper- gans which are suitable for transplantation, ative techniques and all procedures to avoid because of shared biomedical or physiologi- rejection reactions were mostly developed in cal properties. For anatomical and physiolog- animal experiments. Future developments ical reasons, the domestic pig is currently re- are also dependent on preclinical studies garded as the most promising organ donor with animals. The aim of these experiments for man. Animal experiments are therefore is to improve patient care and to prolong the an important interface to research on farm period for which the donated organs function. animals. Methods of suppressing immune reactions The possibility of xenotransplantation is against donated organs must be developed a currently controversial issue. Rather than which minimise the complications suffered a permanent transplantation, another possi- Man or animal? by the recipient. Another objective is to im- bility is to employ xenotransplantation as an Operations in animals and prove the necessary surgical techniques and emergency procedure, if no suitable human in man are about equally the conservation of the donated organs dur- organ is available at once. Current research technically demanding ing transport. in this area is at a very early stage. 3 The term xenotransplantation (from the Greek xenos = foreign) means the transplan-

Cell and tissue replacement in man

any of the diseases known today are tissue (skin or nerve cells) or of biomechan- due to the loss of cells or tissue, or ical systems (heart valves, artificial hearts, Mloss of their function. In degenera- heart pacemakers, artificial joints) are pro- tive diseases, such as Parkinson’s or Alzhe- cedures based on animal experiments. Arti- imer’s diseases, and also in accidents, myo- ficial culture of replacement tissue from the cardial infarction and arthrosis, there is loss patient’s own body is known as “tissue en- of cells and tissue, with major consequences gineering” and it is possible that this may be for the patient’s quality of life. Drug treat- used in the future to replace lost cells or tis- ment, surgical correction and implantation of sue from the patient’s own body. Stem cells

15 Animal Experiments in Practice: Areas in which experimental animals are used

have already been successfully applied to and functions are combined with electronic or bone marrow transplantation. This approach mechanical implants. New developments are offers the possibility of allowing some types also to be expected in the area of biosensors of tissue to regrow. Moreover, in the so-called (implantable electronic aids for seeing and “biohybrid implants”, the body cell structures hearing). 3

Stem cell research

he aim of stem cell research is to deci- Initial successes have also been achieved pher the principles of cell differentiation in the treatment of paraplegically paralysed Tand to establish the possibilities of in- rats. Embryonic stem cells from the brain fluencing this. Stem cells are cells which are were capable of forming a type of bridge be- still largely capable of dividing and devel- tween bone marrow stumps, re-endowing oping. The “totipotent” cells can do every- the animals with limited mobility. Animal ex- thing, from which complete living creatures periments have also been used to win initial can develop. The current view is that this no knowledge on the possible potential for differ- longer applies to “pluripotent” embryonic entiation of tissue stem cells. There is evidence stem cells, although these still have a versa- that stem cells from the bone marrow develop tile potential for development. This also ap- in the brain into nerve cells, which resemble plies to the “adult” stem cells from fully de- the other neurones in the central nervous sys- veloped organs, such as bone marrow, skin or tem. One long term objective is to use human the central nervous system, which can repair stem cells to culture complex cell structures or damage in the organism. complete organs for transplantation. Progress In vitro experiments Animal experiments have a long tradition in this area would greatly decrease the risk of with mouse stem cells in developmental biology, which has studied intolerance and rejection reactions. In culture media, embryonic this theme intensively. One objective of bio- The potential for stem cells and their pos- mouse stem cells differentiate medical research is the development of new sible medical uses are immense. However, into structures resembling therapeutic approaches for diseases which more studies in cell biology and animal ex- are currently still incurable. Thus, the transfer periments are needed to sound out the possi- liver cells, which are capable of stem cells from the pancreas of adult mice bility of using embryonic and adult stem cells of producing the proteins can influence type I diabetes in mice. to heal tissue damage. 3 albumin (green) and alpha-1-antitrypsin (red).

16 Animal Experiments in Practice: Areas in which experimental animals are used Genome research, mutagenised and transgenic animals

enome research deals with the re- tic approaches for this disease, which is wide- cording and decoding of the function spread in man. Gof the hereditary material in living or- Breeding strains for research on diseases ganisms. This concerns not only the simple including cancer, obesity and deafness have sequence of letters in the genetic code, but, already been established. For example, the more importantly, the function of the genes, same gene is responsible for the develop- as these hold the key to the assembly of the ment of colon cancer in mouse and man and body and to the interactions between different attempts are being made to influence these Tumour therapy in fish organs. To be able to analyse this in a com- degenerated cells. If the platie hybrids are missing plex organism, it is necessary to be able to in- Just as with other animal experiments, the control genes for a tumour duce specific changes in the hereditary ma- the Animal Welfare Act demands that, before gene, melanomas can form in terial. This can be achieved by gene transfer genetically modified animals are produced, or by chemical treatment of hereditary mate- there must be an ethical evaluation and con- the skin. The fish then appear rial (mutagenesis). If there are then changes sideration of the stress for the parent animals to have a very dark pigment in the so-called “phenotype” of an animal - and for the subsequent generations. Opera- and are covered in tumours. its appearance, behaviour, organ function or tions, such as the transfer of egg cells to sur- After three months of treatment blood count - this permits conclusions about rogate mothers or cutting the spermatic ducts with a hormone which prevents the genetic basis for these changes. These ex- in male animals, are performed under anaes- terminal differentiation of the periments employ so-called model organisms, thesia and cause low levels of stress in the in- such as flies, round worms, zebrafish, mice or dividual animals. The degree of stress in the tumour cells, there was a rats. The mouse is especially important in re- offspring is often not predictable. However, drastic reduction in tumour search on human diseases, as the mouse ge- experience has shown that the appearance development nome and the human genome exhibit major of transgenic animals is often hardly differ- similarities. Both the human and the mouse ent – if at all – from that of the so-called wild genome have now been fully decoded. type. Evidently the intact gene or other gene Animals in which sections of hereditary groups counteract the impairment in func- material (DNA) have been specifically mod- tion. In transgenic animals equipped with the ified are known as transgenic animals. One same hereditary material with respect to the goal when establishing breeding strains of inserted characteristics (so-called homozy- this sort is to breed animals with a defined gotic animals), about 5% of the offspring suf- loss of function. Researchers have succeeded fer from losses in function. The severity of the in identifying genes which are involved in stress can range from slight to severe. Em- the origination of diabetes mellitus in both bryonic development can be so badly dis- mouse and man. Using the mouse strains, it turbed that the embryos or foetuses die be- has been possible to develop new therapeu- fore birth. 3

17 Animal Experiments in Practice: Areas in which experimental animals are used Transferability of the results from animal experiments to man

he components of body cells and the bio­ possible. This underlying assumption applies chemical mechanisms necessary for the to both the desired and undesired or toxic ef- Tprocesses of life exhibit very marked sim- fects of a substance. Animal experiments make ilarities between different animal species. Mo- it possible to predict the desired and about lecular genetics can demonstrate that all or- 70% of the undesired effects which affect man. ganisms living today had the same origin. One example is acetylsalicylic acid (the active They share genes which are responsible for substance in the analgesic Aspirin®). This al- body structure and which are modified dur- leviates pain in both rat and man, but can in- ing the course of evolution, thus providing the crease the bleeding tendency in both species. material basis for the sequence of living crea- Other examples are the effects of building ma- tures during all ages of the earth. These sim- terials and of solvents, which have damaging ilarities even allow comparisons between hu- effects on both rats and man. Asbestos causes man genes and metabolic processes with those lung cancer in both and plastic solvent liver of bacteria, fungi and yeasts. It may therefore cancer in both. This experience allows the con- be assumed in principle that interventions in clusion that safety and efficacy tests in animal general metabolic pathways will produce ef- experiments permit a considerable reduction fects which are transferable from microorgan- in the risk of new treatment methods in man. isms to animals to man. The Thalidomide catastrophe in the 1960s However, body functions are much more made it tragically clear that testing substances complex in higher animals and man than in the in animal experiments does not always lead to lower organisms, as body functions in higher complete safety in man. Before then, no-one animals are based on a multitude of special- had recognised the possible reproduction tox- ised cell types and organs. For example, an ac- icity of this substance. tive substance may have the desired effect in The transferability of results from ani- the liver, but be chemically modified by the mal to man also applies in the opposite di- liver cells in such a way that a compound is rection. Drugs which have been successfully formed which is toxic for the central nervous used in man can also be used for domestic an- system. This shows that the transfer of reaction imals. The basic assumption of transferability patterns from cell structures to the total organ- is also an important aspect in the evaluation of ism can be extremely difficult. For this reason, pain and sensitivity in animals. The anatomi- not only studies at the cellular level are needed cal structure of the brain and the conduction of (complementary methods), but also always ex- pain stimuli and their perception in the central periments with the complete organism. Be- nervous system are similar in higher animals. cause of the similarities in cell and organ struc- This therefore permits analogies to be drawn ture in different mammals, it is assumed that about pain sensitivity and about the possibil- transferability from animals to man is mostly ity of suffering. 3

18 Animal Experiments in Practice: Areas in which experimental animals are used Veterinary research

he results from animal experiments are in animal experiments. However, veterinary not only of use in human medicine, but medicine cannot dispense with the use of ex- Talso in the development of new diagnos- perimental animals in basic research and in tic and therapeutic procedures in veterinary the development of new treatment methods. medicine. One example for the use of treat- The studies are mostly planned so that ani- ment methods from human medicine is tumour mals are involved in the studies for which the therapy in small animals. Transfer is generally procedure is subsequently to be used in prac- possible without difficulties, as the procedures tice. The study is performed on the target spe- practised in human medicine were developed cies – the potential patient. 3

Laboratory animals help our domestic animals Studies are often performed and new therapeutic procedures tested on the animals which are to be the patients in the veterinary practice.

19 Animal experiments & animal protection: An ethical balance Animal experiments & animal protection: An ethical balance Is it possible to dispense with animal experiments?

ince the first use of animal experiments This might justify the accusation of hypoc- in research, opponents have often de- risy. Smanded that they should be partially or One reason that it is impossible to dis- fully abandoned. Instead, they point out the pense with animal experiments totally in possibilities of natural medicine or the medi- Germany is that many experiments are per- cine of other cultures, even though the meth- formed because of national and international ods and efficacy of these treatments have legal regulations. These include chemicals generally not been scientifically proved. In laws, drug guidelines and environmental Hygiene is the first command- contrast to so-called experience or alternative laws. Legislators have prescribed these sub- ment in the animal house medicine, conventional European medicine stance tests to protect the consumer and for Before entering the animal seeks causally based therapy, to understand risk assessment. The current requirements for the clinical course of the disease and to be the approval of a drug include animal exper- house, animal keepers and sci- able to develop new methods of treatment. iments to test entists must put on masks, to Dispensing with animal experiments 4 Acute (immediate) toxicity, exclude the risk of infecting the would slow medical progress in an irrespon- 4 The effects of lower doses applied over a animals. sible manner and markedly decrease the longer period – the chronic toxicity, chance of a cure for sick people. Biomedical 4 Its carcinogenic activity, research is currently in a state of rapid de- 4 Its effect on unborn life, the teratogenic velopment and a multitude of new insights activity. are to be expected in the coming years with These tests are only possible in the intact the use of new methods. If Germany acted organism. Nevertheless, partial aspects of alone and dispensed with animal research, it these tests can be submitted to a preliminary would very rapidly lose contact with interna- study in cell cultures. Research has devel- tional research and the immediate access to oped alternatives, which reduce the number the findings. If the animal experiments were of animal experiments and avoid that animals shifted to neighbouring countries, this would suffer unnecessarily. In many cases, it has have no effect on the overall numbers of ani- been possible to reduce the necessary extent mal experiments or on the experiments them- of safety testing by adapting national and in- selves. This would only mean displacement to ternational laws. Thus, the so-called LD50 countries where the regulations are less strict. test to test acute toxicity is still demanded in This would not improve the protection of the the international guidelines. In these test se- individual animal. We can assume that med- ries, the concentration of a substance is de- ical progress from exported animal experi- termined at which 50% of the animals in one ments would also be exploited in Germany. group die. 3

21 Animal experiments & animal protection: An ethical balance Are there alternatives to animal experiments?

he demand for “alternative methods” or a reduction in the numbers of animal experi- “replacement methods” for animal ex- ments. This is particularly the case in the areas Tperiments has become increasingly stri- of drug testing and in drug development. dent in recent decades. Ideally, these would The demand for alternative methods has be methods which would allow the use of an- a different significance in basic research. An- imals to be fully abandoned. The talk here imal experiments are necessary here for the is mainly of work with cell lines. This is in- clarification of physiological connections and deed the ideal case - in the sense of wishful their disturbances in the organism. These in- thinking - as the complexity of an organism, clude studies on the central nervous system with the interactions between organs and tis- and the processing of sensory stimuli, inter- sues, can never be fully replaced by artificial actions within the cardiovascular system, the systems. Even now, experimental methods digestive system, the hormone system, the outside the organism, the so-called “in vitro immune system and behavioural principles. methods” (in vitro = in test tube), are of ma- When checking the approval of animal ex- jor importance in research and in public sup- periments, the authorities examine whether port of research. Cellular and molecular de- the experiment is essential or whether the de- tails of drug action and metabolism can be sired results can also be attained without us- clarified in this way. In recent decades, great ing animals. progress has been made in the methods used Computer simulation can be a comple- in “in vitro” systems. Nevertheless, in spite of ment to animal experiments. This is used in these improvements, the intact organism can- biomedical research to depict and map hy- not be replaced and its reaction must even- potheses about processes and to check them tually be clarified in vivo (in life), i.e. in ani- on the basis of theoretical models. This tech- mal experiments. This is why both basic and nique is frequently used in neurobiology, to industrial researchers study biochemical de- portray the functions of the central nervous tails in vitro, but usually follow these studies system. However, the conclusions of the sim- with animal experiments, to clarify the links ulation must always be checked in animal ex- within the organism. The two approaches are periments. Computer simulation is also used complementary. in higher education, to analyse complex bio- Animals must be killed to produce organ logical situations, to demonstrate them to stu- and cell cultures. Human and animal cell lines dents and to exemplify the information about may change over time after storage and cul- animal experiments beyond the content of ture for many generations. Moreover, they only textbooks. The design and performance of permit the analysis of specific biochemical de- animal experiments can also be demonstrated tailed questions. For the culture of cell lines, in learning videos. These simulations then calf serum from slaughtered animals is often serve as teaching aids and as preparation for needed as nutrient, to stimulate cell division, working with living animals. Their aim is to growth and differentiation. Studies on cell cul- increase sensitivity when working with ex- tures and cell lines have nevertheless led to perimental animals.

22 Animal experiments & animal protection: An ethical balance In Germany, the Centre for Documenta- responsibility of the European Centre for the tion and Evaluation of Alternatives to Animal Validation of Alternative Methods in Rome Experiments (ZEBET) in the Federal Institute (ECVAM). European Guideline 67/548/EEC for Risk Assessment in Berlin was founded to (Annex 5) lists alternative methods which record and evaluate replacement and com- permit the phototoxicity or corrosive effects of plementary methods for animal experiments chemical substances to be examined on cell and of achieving their recognition if possible. culture models. These tests must therefore no This institution is also the centre for provid- longer be performed on animals within Eu- ing information on alternative methods and rope. There are efforts to have these test pro- is meant to further the validation of meth- cedures accepted throughout the world and ods without experimental animals. This is have them included in the guidelines of the needed to achieve inclusion in the interna- OECD (Organisation for Economic Coopera- tional testing guidelines for safety toxicol- tion and Development). 3 ogy. At the European level, this work is the

Limits to alternative methods

n spite of favourable aspects, these meth- be inactive or even toxic in other cell types, or ods possess a severe disadvantage. The hu- lead to the formation of breakdown products Iman or animal body possesses more than in the body, which cause damage in other or- 200 different cell types and the interactions gans. The complementary character of an- of these are coordinated in organs and tissue imal experiments and alternative methods structures. To study this complexity is an im- nevertheless offers the chance of greatly re- portant part of biological research and this ducing the number of animal experiments. In can only take place in the intact organism. particular, this is possible in tolerance studies Even if a drug appears to be useful during its for man and the environment. 3 development in cell culture, it may turn out to

23 Animal experiments & animal protection: An ethical balance The three Rs

Reduction lthough animal experiments remain The objective in basic research is that an- Refinement essential in biomedical research, there imals should only be exposed to low levels of Replacement Ais a general consensus that they must stress if possible. This allows for ethical ob- be restricted to the necessary minimum. The jections to animal experiments and improves three Rs - reduction, refinement and replace- the quality of the test results. Research work- ment of animal experiments – can be taken ers are continually called on to optimise their as the guideline. Consistent application of methods and to evaluate the extent of neg- statistical procedures and exact experimen- ative effects on the animals, on the basis of tal planning serve to reduce the number of objective parameters, such as the animals’ animals. This is supported by the fact that behaviour. This requires both personal sensi- the official approval and publication of the tivity and good training. research results in professional journals are The European Science Foundation (ESF) Improvements in measure- linked to the demonstration that the results in Strasburg is the umbrella organisation for ment techniques and expertise are statistically significant and that the stud- all state organisations to support research in ies are original. The refinement of animal ex- Europe and has issued a policy paper with in handling of animals help to periments has the objective of minimising the recommendations for work with experimen- reduce the stress on the individ- adverse effects on the animals from the stud- tal animals. This appeals to members to ac- ual animal. This helps to reduce ies. Great progress has been made in elimi- cept the principles of the three Rs and also the numbers of experimental ani- nating pain by analgesia and anaesthesia, in to undertake specific efforts to reduce and to mals and is in keeping with the technical improvements in measurement pro- improve animal experiments. 3 concept of the three Rs. cedures and in the development of non-inva- sive study methods.

Acceptance of animal experiments

n independent opinion research insti- This becomes clearer once the purpose tute has evaluated and assessed nine of the research is intelligible. In this case, Astudies performed throughout Ger- 10-11% of those questioned supported the many in the 1980s and 1990s. performance of animal experiments without This study showed that animal experi- reservations. With some reservations – de- ments which serve the good of mankind were pending on the purpose of the experiments – accepted by most of those questioned. 71-75% of those questioned tolerate the ani-

24 Animal experiments & animal protection: An ethical balance uncertain EMNID '85 EMNID '86 mal experiments (EMNID 1985, 1996). As commission- Results of the EMNID and AllensbachAllensbach polls '92 For example, in the 1993 study performed ed by the DFG and against by the Allensbach Institute, 50% of those the Max Planck So- questioned supported animal experiments, ciety, a poll of ex- uncertain EMNID '85 if human life could be saved with their help; perts was performed EMNID '86 it depends 24% could not decide and 26% tended to op- in 1999 on the is- Allensbach '92 pose animal experiments. sue of animal ex- against pro Many of those questioned did not con- periments. The ex- nect scientific experiments with torturing an- perts came from the 0 % 20 % 40 % 60 % 80 % imals. 30% had no general reservations about fields of econom- it depends animal experiments; for 49%, it depended on ics, science, politics, the type of experiment (EMNID 1985, 1989). the press and animal pro Hardly any of those asked considered that protection. The re- there were superfluous areas of medical re- sults of the poll show 0 % 20 % 40 % 60 % 80 % search. In addition, more than 75% were not that there is a great prepared to forfeit the development of new demand for informa- drugs to prevent the use of animals (EMNID tion on animal ex- 1985, 1986, 1989). perimental research Results of the GfM GETAS poll (1993) Animal experiments are required by the within society. The legislator for testing pharmaceuticals and dominant impression other medicinal products before they are ap- in the population is pro plied in humans. The EMNID polls dealt par- that public research pro 50 % ticularly intensively with the issues of drug institutions oper- pro (with research and animal experiments. The re- ate defensive infor- reservations) sults showed that experiments of this sort mation politics and undetermined are not only tolerated, but even demanded, this was confirmed pro contra (with reservations) by those questioned. The acceptance of ani- by this expert poll. It 50 % mal experiments in drug safety and research is therefore particu- contra is mainly based on the wish for safe and reli- larly important that 26 % contra able medical care. Most of those questioned these institutions 0 % 10 % 20 % 30 % 40 % thought that it was a matter of course that an- should inform the imals were used for the good of man. 75% of public about animal contra those questioned in the EMNID poll (1985) experiments, as the public has a great deal of 26 % Attitude of the population and about 50% in the GfM GETAS Study trust in the independence of the Max Planck to animal experiments (1993) could not conceive of doing without Institutes and universities, in comparison0 % 10 to % 20 % 30 % 40 % meat products. Although the use of animals commercially orientated industrial research. as food was unambiguously advocated, most It has been shown that firms and research of those questioned were unwilling to express institutes enjoy greater acceptance if they a clear opinion on the use of animals in ex- maintain intensive dialogue with the popula- periments. tion about their animal experiments. 3

25 Animal experiments & animal protection: An ethical balance The development of ideas on animal protection in Germany

he idea that man has a special responsi- of animals was demanded. Religious groups bility for animals in his care is the result coupled their disapproval of animal experi- Tof the historical development of the rela- ments with their rejection of scientific ideas tionship between animals and man. Cultural, on progress. However, the opinions of phy- philosophical, social and official standards sicians were also divided and some consid- define the limits of our attitudes to animals ered that animal experiments were an unsuit- and their needs. If current laws and regula- able way of solving medical problems, as they tions on animal protection are considered, it doubted the transferability of the results. becomes clear that these are based on a basic The first German Animal Welfare Act conception of ethical animal protection. was passed in the 1930s and this remained Since the 17th century, an anthropocen- in force till after the Second World War. This tric view of animal protection has been evi- laid down regulations for working with ex- dent – with man as the centre. In the 18th and perimental animals for the first time. In the Operation on the open chest 19th centuries, influential members of a so- 1960s and 1970s, public discussion of the cially and politically active class of the popu- safety of farm and experimental animals Ferdinand Sauerbruch lation became active. They loathed all forms was revived. This encouraged the creation successfully used the so-called of pain to animals and regarded this as a mark of new laws on animal protection. The Ani- pressure difference procedure of their level of culture - the animal protec- mal Protection Law passed in 1972 is based to prevent the collapse of the tion movement. The focus of interest was not on ethical concepts of animal protection and lung in the opened chest. the animal, but concerns about the brutali- exploited scientific knowledge on species- The first trial operations took sation of individuals and of society. As Ger- specific and behaviourally correct standards many consisted of many small states, a variety and the needs of the animals as criteria for place in the dog. With this of laws were passed. National criminal legis- evaluation. Subsequent changes in the law in method, operations on the heart lation on the protection of animals from cru- the 1980s and 1990s were influenced by eco- and lung were possible elty was only passed in 1871. This standardi- nomic, scientific and political considerations. for the first time. sation of the law supported animal protection These changes increased the emphasis on as a social goal and led to the formation of nu- animals as creatures like man and increased merous societies for animal protection, with the strictness of the regulation of animal ex- the objectives of preventing cruelty to ani- periments. To enhance the protection of an- mals and “vivisection” (operations on living imals as living creatures in the legal system, animals). As experimental research and con- animal protection was laid down as an offi- sequently the number of animal experiments cial goal in the national constitution. This was increased within the same period, this inevi- added as an addendum to the constitution in tably led to conflict between science and an- July 2002 under § 20a. This legal status is imal welfare. Various different reasons led to unique anywhere in the world; the demand the rejection of animal experiments. Either that man deals with animals in a morally re- animal experiments were totally rejected for sponsible manner has thus acquired an unu- ethical reasons, or a reduction in the numbers sually high status. 3

26 Animal experiments & animal protection: An ethical balance Ethical aspects of animal experiments and the principle of solidarity

Karin Blumer

he question of the ethical acceptabil- which assume, for example, that nature is ity of scientific animal experiments was “animated”. The Nobel Peace Prize winner Tfirst systematically discussed in philo- Albert Schweitzer developed the concept of sophical ethics in the 1970s. The discussion radical biocentrism, which includes all forms was mainly triggered by the writings of the of life in the moral community. Although this Australian philosopher Peter Singer, who laid appears plausible at first sight, it is based on the foundation for the new movement on an- an extremely deontological standard. It for- imal protection with his 1976 work - Animal bids the damage of all forms of life - whether Liberation. Philosophy has been occupied for animal, plant or bacterium - and thus places centuries with the question of man’s respon- the active agent before irresolvable dilem- sibility for non-human life. Philosophers have mas. used various theoretical approaches to ad- Finally, pathocentrism, as propagated by dress the complex theme of the relationship Peter Singer and many other proponents of between animals and man. animal protection, is incapable of provid- In classical anthropocentrism, animals ing a clear proof as to why only animals with have no inherent value at all; this can now an intact central nervous system may pos- be regarded as out-dated. It was traditionally sess an inherent moral value. What however supported by such important philosophers as is a much greater problem is the proposal by Aristoteles and Immanuel Kant, together with many pathocentrics that some animals should the Christian moral theologians. Its basic as- be declared to be “persons” and to refuse to sumption is that only man is worth protection, accept the personality of some humans. Pe- as only man is a rational and reasonable be- ter Singer has been particularly prominent ing (or in the image of God). This led to the on this issue. For him, great apes, whales and Albert Schweitzer (1875-1965) justified accusation of speciesism, first made dolphins are certainly, and all other mammals His radical biocentrism includes by Jeremy Bentham in 1789. Bentham proved very probably, persons, whereas newborn ba- that this was egoistic group behaviour, as bies, persons with severe mental handicaps all living creatures in the moral solely the membership of the biological spe- and comatose persons are degraded to “mere order. According to this, harm to cies Homo sapiens served as the ground for members of the species Homo sapiens”. any form of life - whether ani- justification. At least since the general ac- “Moderate biocentrism” or “moderate mal, plant, parasite or bacterium ceptance of the theory of evolution in the mid anthropocentrism” is a moral theory which – is forbidden. 19th century, the thesis of man’s biological might be widely acceptable and plausible uniqueness can no longer be maintained. these days. Both theories ascribe a moral sta- However, many other ethical positions tus to all forms of life, although the binding on the relationship between animals and inherent value of this increases with the po- man are equally unsatisfactory. Thus, ho- sition of the species on the evolutionary lad- lism, which demands an independent right of der (hierarchy of the organisms). Thus, for ex- existence for even mountains or rivers, suf- ample, there would be more reason to protect fers from its highly metaphysical premises, the health of a dog than of a hamster or of a

27 Animal experiments & animal protection: An ethical balance worm. However, the human being retains a } The increase in knowledge can be achieved special position even within “moderate bio- in no other manner. Alternative methods centrism” or “moderate anthropocentrism”. cannot be used. A principle objective of philosophical } This is not an unjustified repeated experi- ethics is to develop standards for human ac- ment. } No more animals are used than is abso- tions and to provide reasons to justify these. lutely necessary. On the basis of formal guidelines, every vio- } The animals used are as low on the evolu- lation of animal interests must be justified by tionary ladder as possible. a balanced consideration of values. This does } No avoidable harm is inflicted on the ani- not only apply to animal experiments, but to mals. This particularly applies to care, hus- all actions in which animals are used for hu- bandry and possible use of analgesia. man requirements. Committees on animal protection comply Animal experiments have a special sta- with these guidelines when approving ani- tus in the discussions of the relationship be- mal experiments. tween animals and man. This is not only This argumentation is also both permissi- because many people regard them more crit- ble and necessary for animal experiments in ically than, for example, slaughter of animals basic research. The fact is often overlooked for meat or the specific breeding of beauti- that the balanced evaluation does not sim- ply compare the interest of the animals with ful but anatomically or physiologically sick the increase in knowledge as an aim in it- races. A much more important consideration self. It is rather the case that the interests is that the motive of the scientific animal ex- must be included of the innumerable peo- periment is to increase knowledge. This in- ple who suffer from diseases which cannot crease in knowledge is by no means an end in be treated or cannot be treated adequately. itself, but has a concrete objective: the main- With these premises, a massive restriction tenance and furtherance of the health and in biomedical research, as is sometimes de- According to Aristoteles quality of life of men and animals and the in- manded, becomes ethically indefensible, as (384-322 B.C.) possess both a crease in the knowledge of nature. Although not only actions, but their omission, must be “vegetative” and an “animalistic” this goal cannot be attained in each indi- morally justified. It would only be conceiv- able to dispense with animal experiments soul. They are capable of fulfilling vidual experiment, philosophical considera- completely, if increases in scientific knowl- their own needs in a deliberate tions indicate that it possesses greater value than, for example, excessive supplies of ani- edge in wide areas of biomedical research manner, but cannot act could be sacrificed. This sacrifice would be of mal proteins to people in industrial countries reasonably. Arthur possible therapies for many diseases, which or the aesthetic demands of the owners of do- Schopenhauer (1788-1860) are not peripheral phenomena, but very com- mestic dogs or cats. As in our society an in- considered that animals possess mon. These include cancer, HIV infection and crease in knowledge possesses a high moral AIDS, cystic fibrosis, cardiovascular diseases the same characteristics as man. value, animal experiments can be justified if and Alzheimer’s and Parkinson’s diseases. This means that they are capable the following conditions are fulfilled: A complete prohibition of experimental of suffering and feeling. } The increase in knowledge is essential and animal research would also be in conflict with serves ethically justifiable objectives. another valid fundamental moral standard,

28 Animal experiments & animal protection: An ethical balance the solidarity principle. This describes the sions when we are compelled to violate one principle of providing the best possible sup- obligation. As long as it is scientifically im- port to all those requiring help - the weak and possible to unravel complex causal activity the sick. The solidarity principle is not only relationships in living animals without ani- one of the many preconditions for life in hu- mal research, this conflict between obliga- man communities; it is a special characteris- tions will remain the theme of ethical discus- tic of man as a morally responsible being ca- sions. There will never be a general answer pable of solidarity. to the question of whether an animal experi- People who perform animal experiments ment is justified. Only specific individual an- always experience conflict between two ob- swers are possible. 3 ligations. The first of these is positive and is the obligation to use one’s own knowl- edge and abilities to reduce human and ani- mal suffering. In contrast, the negative obli- gation is not to inflict avoidable suffering on The author is a veterinary physician, has a doc- other creatures. In the context of human ac- torate in philosophy and currently works in the tivity, we often find it difficult to reach deci- pharmaceutical industry.

29 Animal experiments in Germany: From application to performance Animal experiments in Germany: From application to performance European regulations on animal experiments

s part of Europe, Germany is bound by nity. This expresses the wish to ensure that the laws of the European Union. This animal protection is improved and that the Aapplies to both the laws on animal pro- well-being of animals, as sentient creatures, tection and to the regulations on the perform- is considered. For example, the Community ance of animal experiments. may couple the award of research funds to qualitatively high standards of animal exper- Council of Europe iments. The same is expected when member The Council of Europe is a regional organisa- states award research funds. According to tion for all of Europe and has the general po- this, the influence on the issue of animal ex- litical responsibility of implementing the com- periments is a result of the Community’s au- mon political ideals of the member states and thority to standardise legislation. This is the of furthering their collaboration. The Council basis on which the “Council Directive on the of Europe considers that this includes environ- approximation of laws, regulations and ad- mental protection, which also covers the theme ministrative provisions of the Member States of animal protection. With this background, regarding the protection of animals used for the “European Convention for the Protection experimental and other scientific purposes“ of Vertebrate Animals used for Experimen- of 24 November 1986 (86/609/EEC ABl. No L tal and other Scientific Purposes” was passed 358, p. 1) was passed. The legal force of this on 18 March 1986. This is a multilateral con- directive in individual EU countries depends on tract in international law, which requires rat- its implementation by national legislators. 3 ification. As a consequence of the ratification of 11 December 1990 (BGBl. 1991 II, p. 740), Animal experiments in Germany this agreement became binding for Germany. Approval Performance Monitoring The German Animal Welfare Act is in accord- ance with these Council of Europe guidelines Approval agencies for the area of animal experiments. depending on the federal Approved Monitoring authority state: Government com- projekt Control Veterinary office European Community mittee, district govern- Approval/ ment Rejection The contract law for the European Commu- nity also contains community authority for Proposal/Call animal protection, under the aspect of envi- Applicant Control ronmental protection (Art. 174 EU Contract). Member of a scientific advises appoints Clause 10 of the Amsterdam Contract of 2 Oc- research institute tober 1997 is entitled “Protocol on protection advises and welfare of animals” and this is a binding Animal Protection Committee Animal safety officer component of the primary law of the Commu-

31 Animal experiments in Germany: From application to performance

Animal experiments with the preconditions of approval

o-one can build a house without build- ble if this is in favour of constitutionally pro- ing approval or run a restaurant with- tected objects of legal protection. Since July Nout a licence. It is equally true that no- 2002, this constitutional justification has been one can perform animal experiments without supplied by Article 20a of the constitution, approval. This is a so-called “preventive pro- with the formulation “and the animals” in the hibition”. This implies that animal experi- context of the national goal of “the environ- ments are permitted in principle, but may be ment”. This makes it clear that the Animal Testing heart valves forbidden in specific cases, if the legal pre- Welfare Act can constitutionally restrict free- After implantation of the conditions are not met. To allow regulation dom of research. by the authorities, the performance of an ex- However, this makes no difference to the heart valves, the operated sheep periment is preceded by an approval proce- objective or legal character of the current reg- are returned to the herd and dure (§ 7 of the Animal Welfare Act). ulations. As animal protection is a national can continue to live in their The constitution guarantees scientific free- goal in the context of the constitutional order, accustomed social environment. dom. However, the preventive prohibition re- it is an exclusive duty of the legislator to rec- The implant function is medically stricts the researcher’s freedom. In accordance oncile freedom of research and ethical animal monitored. with the principles of constitutional protection protection. This duty has been addressed by of basic rights, this must be justified. For con- the legislator with §§ 7 to 9 of the Animal Wel- stitutional rights - like scientific freedom - for fare Act. The approach has been effective, al- which no reservations were planned by the though it is somewhat less secure with respect legislator, legal intervention is only permissi- to the dogma of the constitution. 3

Interpretation of the Animal Welfare Act for the area of animal experiments

f animal experiments require approval, it An animal experiment has the following char- must be clear what an animal experiment acteristics: Iis. The definition of animal experiments is } The purpose of the experiment: The ob- based on the purpose of the law as laid down jective of the experiment is to gain knowl- in § 1 of the Animal Welfare Act. According edge. There is no gain in knowledge if the to this, no-one may inflict pain, suffering or question put has already been clarified; damage on an animal, without a good rea- } The operation or procedures on the animal son. The approval procedure, in accordance may be linked to pain, suffering or damage, with the Animal Welfare Act, will then test } The operation or procedure on the animal whether there is a good reason that pain, suf- may be linked to pain, suffering or damage fering or damage are inflicted. for the genetically modified animals or their carriers.

32 Animal experiments in Germany: From application to performance

According to the German Animal Welfare chemical or other hazardous substances Act, the purposes of animal experiments may – in basic research. be lawful, absolutely unlawful and principally } Animal experiments are absolutely unlaw- unlawful. ful, if they are related to the development } Animal experiments are lawful, if they are and testing of weapons, munitions and related to knowledge of human or veteri- linked equipment. nary medicine, for example } Animal experiments are principally unlaw- – In the development of new drugs, ful, but with the possibility of specific ex- Principles of orientation – In detecting environmental risks, ceptions, if they are related to the devel- Like bees, locusts find their – In testing the safety of drugs, pesticides, opment of tobacco products, detergents or orientation from the pattern plants, foods or consumable objectives, cosmetics. 3 of polarisation in the sky

What is the legal definition of “essential”?

t is expected that the researcher will col- there is any other procedure which allows the lect information on the status of current re- animal experiment to be dispensed with. Isearch when planning his experiment and All accepted results must be considered, will consider whether his planned study may including minority opinions, if they are of ad- lead to new knowledge. An experiment is equate scientific quality. The essentiality only “essential” if there is no equally valid must not only be checked for the lawfulness alternative, given the planned purpose. On of the animal experiment (“whether”), but the basis of available scientific knowledge, also for the specific procedure (“how”). The it must accordingly be considered whether principle of the three Rs applies to both. 3

What is the legal definition of “ethically justifiable”?

hen considering ethical defensibil- tained in laws related to animal experiments ity, the stress to the experimen- – such as the Drug Law, the Hazardous Sub- Wtal animal during the experiment stances Regulation, the Pesticides Regulation must be balanced against the question as to or laws on waste water. These no longer re- whether this is justified by the increase in sci- quire approval and illustrate specific evalua- entific knowledge. The evaluation of the ex- tion of the relative benefits and stresses. The periment must then weigh the expected bene- performance of these experiments is based fit against the expected burden to the animal. on the purposes of these laws and the de- Undisturbed measurement In the specific case, this is a difficult decision. mands of our society. In the final analysis, The marmots’ body temperature Additional measures for ethical defen- society decides which risks it is prepared to and oxygen consumption are sibility are provided by the standards con- tolerate. 3 measured during their winter sleep. 33 Animal experiments in Germany: From application to performance Approval procedure

efore an animal experiment can be per- possess the necessary professional qualifi- formed, it must be reported to the re- cations and be personally reliable. This im- Bsponsible authorities and approved by plies that they may not have violated the them. The notification or application must in- Animal Welfare Act in the past. clude comprehensive scientific details and expert documentation. The approval proce- } Facility-related: The personal and structural dure must include three elements for the ap- preconditions for the performance of the an- plicant to be granted or refused permission. imal experiment must be given. These in- clude qualified animal keepers, suitable } Project-related: The project must be scien- rooms for keeping animals and the desig- tifically justified and the essential charac- nation of an animal safety officer. For ani- ter and ethical defensibility demonstrated. mal husbandry, care must be taken that the In addition, the desired experimental result experimental animals are kept in a manner may not be already available from other which is suitable for their species and needs sources. The appropriate authorities (such and that their medical care is guaranteed. How do you move as ministries or state government offices) through rough territory, are responsible for evaluation and they If the preconditions are fulfilled, the author- without falling over? check the plausibility of the application. In ities must award the approval within three The stick insect is used as the course of their decision, the authorities months. The approval is for a limited time pe- a model in the decoding are not to replace the authors’ scientifically riod and may be linked to conditions. Should plausible description of the value of the ex- violations be established and where there is of coordinated movements. perimental objective with their own views. due reason, financial penalties of up to 25,000 Results from these studies are Euro or prison sentences may be imposed. used in robot technology. } Person-related: The responsible manager Prohibitions to perform animal experiments of the research project and his deputy must or to keep animals are also possible. 3

Performance of animal experiments

The guiding principle of essentiality (§ 9 Ani- } Experimental animals must be specially bred. mal Welfare Act) also influences the perform- The use of stray dogs and cats is forbidden in ance of the experiments: Germany and “animal catchers” may not sell } Experiments on animals with “advanced animals they have caught to laboratories. nervous systems” may only be performed when experiments on animals without ad- } Experiments on animals taken from nature vanced nervous systems are inadequate. are only allowed if specifically bred ani-

34 Animal experiments in Germany: From application to performance

mals are not available. They require special permission. } Major operations may not be performed more than once on vertebrates. } More animals may not be used than neces- sary. } If death is expected, the period of suffering must be kept as low as possible. } Pain, suffering and harm may only be in- flicted on the animals to an extent that is } Follow-up medical care must be provided inevitable. Anaesthesia of the experimental by a veterinarian, who can decide after an animals and the obligation to reduce pain experiment whether the animal can con- have priority. tinue to live without pain and suffering. 3

Monitoring of the experiment

ffective monitoring of the animal exper- stitution to further the development and in- iment by the authorities is only possi- troduction to avoid or restrict animal exper- Eble if the experiment is properly doc- iments. When fulfilling his duties, he is not umented. For this reason, the details of the obliged to follow instructions. experiment must be recorded, including the In addition to this internal monitoring, in- number of animals and their species. The stitutions in which animal experiments are previous owners of dogs and cats must be performed are subject to monitoring by the given, to protect strays (§ 9a Animal Welfare responsible veterinary offices. Without prior Act). In addition, § 11a of the Animal Welfare warning, these can inspect documents and Act lays down that the breeder must record take samples. If violations are established, and mark the animals, so that the history of these authorities can give instructions to have the animals can be followed up to the exper- these eliminated. These include instructions iment and beyond. to cease animal experiments performed with- The internal monitoring is performed by out the necessary approval or in contraven- the animal welfare officer, who monitors an- tion of a prohibition in the Animal Welfare imal husbandry and is obliged to comment Act (§ 16a Animal Welfare Act). Violations of on the submitted applications. In addition, he the regulations are regarded as administra- must provide advice to those participating in tive offences, in extreme cases as criminal of- the experiments and be active within the in- fences. 3

35 Animal experiments in Germany: From application to performance Stress during animal experiments

ccording to current scientific knowl- eliminated. Both the duration and frequency edge, the sensitivity of vertebrates of repetition of the procedures must be con- Ato pain is similar to that of man. The sidered in the evaluation. closer the evolutionary relationship is to man, Correct evaluation of the stress to which the more reliable is the assumption that the an experimental animal is exposed assumes animals not only perceive pain, but also suf- familiarity with its species-specific facial ex- fer subjectively. The legislator recognises this pressions and behavioural characteristics, by demanding an evaluation of the conse- particularly in experimental situations. There quences for the animal during the approval are however no international standards to as- of an animal experiment. In accordance with sess this. It is recommended that evaluation the general rules on the Animal Welfare Act, of pain to rodents should be based on the FE- the stress is classified into four degrees (none, LASA report “Pain and distress in laboratory slight, moderate and considerable). To facil- rodents and lagomorphs” (Laboratory Ani- itate the evaluation of this stress, the DFG mals 28,1994; 97-112). Use of new transplantation and the Max Planck Society have performed In some animal experiments, the animal a classification of conventional operations serves as a model for specific clinical presen- procedures and procedures. This was based on the cate- tations in man. Such experiments are of par- So-called minipigs play an gories suggested by H. P. Schnappauf („Kri- ticular significance in biomedical research, important role in transplantation terien für die Beurteilung des unerlässlichen although they may result in the animals ex- surgery, in the development Maßes bei Eingriffen und Behandlungen im periencing pain or suffering. For reasons of of new operative techniques. Rahmen der Hochschulforschung“ [“Cate- animal protection, the expected states of pain These two pigs were submit- gories for the evaluation of the inevitable ex- and fear are alleviated with the help of anal- ted to a lung transplantation, tent in operations and procedures in univer- gesics or sedatives. Experiments coupled to sity research”], Tierärztl. Umschau 39, 1984; high stress are usually performed under to- which they survived without 870-879). Procedures were regarded as be- tal anaesthesia. These are often so-called fi- harm. Today, one year after the ing of low stress if they could be performed in nal experiments, in which the animals re- operation, the animals live in an man without anaesthesia or protective meas- main under anaesthesia and are killed under agricultural unit and are given ures. These include, for example, injections anaesthesia after the tests have been com- regular follow-up controls. and short term fixation of the animals. Meas- pleted. ures causing intermediate or moderate stress The criticism is often made that possi- were those which humans would judge as ble fluctuations in stress within the experi- unpleasant, but not damaging to tissue. This ment are not allowed for and that the emo- also includes operations under anaesthesia tional state of the individual animal is not which lead to low consequent stress, such as considered. However, intense stress or states laying an in-dwelling catheter. Considerable of fear influence all organic functions and af- stress was split into two subclasses. The stress fect the results of the study. Results from ex- is high when pain requiring analgesia can periments with frightened or suffering ani- be expected after the operation. The stress is mals are scientifically worthless and are not very high when the resulting pain cannot be accepted internationally in basic research. To

36 Animal experiments in Germany: From application to performance obtain reliable experimental results, it is es- pain and fear, if possible. Scientific interests sential that the experimental animals are in and animal welfare are therefore not in op- a normal physiological state and are free of position. 3

Who is allowed to perform animal experiments?

he most important guarantee that ani- cially trained biology technicians or labora- mal experiments are properly performed tory animal keepers, who have been individ- Tis that the scientist and his personnel ually examined. There are additional severe are well trained, cautious and sensitive to the restrictions on the persons who may perform needs of the animals. According to the Ger- operations. These may only be performed by man Animal Welfare Act, animal experiments veterinary surgeons, doctors or biologists spe- may only be performed by persons with the cialising in zoology. They must be employed requisite knowledge. These are persons with in scientific institutions. Specific exceptions a university degree in veterinary medicine, may only be approved after professional medicine or natural sciences, or persons with qualifications have been examined. 3 specific professional training, such as spe-

How is the training performed?

vailable training in working with ex- FELASA (Federation of European Laboratory perimental animals differs greatly in Animal Science Asso-ciations, London). Up to Adifferent universities. There are no 80 hours of comprehensive advanced training current binding training plans for the differ- (for study managers) are recommended, de- ent federal states. Students are generally pro- pending on individual responsibility. vided with the necessary training during ad- The DFG recommends that training of- vanced practical courses and lectures at the fers of this sort should be taken up and university or in courses presented by scien- can accordingly provide financial support for tific societies. The training can be orientated postgraduate training for young scientists. on the recommendations of the Council of For example, the Centre for Animal Welfare Europe for the training, further training and in Hanover University and the Animal Protec- postgraduate training of persons engaged in tion Information Centre in Munich University work with experimental animals. These rec- regularly offer supraregional training courses ommendations are based on suggestions from at their own initiative.3 the international professional organisation

37 Summary Summary

Responsibility to animals and man

iscussion in society on the pros and isms, such as round worms, or cell cultures, as contras of animal experiments is often so-called alternative methods. Each of these Dvery emotional. The spectrum ranges approaches has advantages and disadvan- from general rejection through the large tages. For example, complex problems, such group of people who accept a restricted as metabolic performance, behaviour or sen- number of animal experiments, to advocacy. sory processing can only be clarified in animal The differences in views become particularly experiments. On the other hand, cell cultures obvious when changes in the Animal Welfare permit detailed studies on strictly isolated Squirrel monkeys in research Act or in the constitution are being discussed. and defined systems. The overall perform- in tropical medicine As research bears responsibility towards so- ance of the organism can however not be re- Monkeys are only rarely used in ciety, it must analyse and discuss these dif- corded. The decision as to which procedure is ferent positions. Animal experiments on risk most suitable for clarifying a specific problem animal experiments in Germany. evaluation of pharmacological and chemical must be made when approaching the experi- They make up only 0.08% of substances are prescribed by national and in- ment. It is not in the interest of science to per- experimental animals. For exam- ternational law. The scientist can act as an form animal experiments when more suitable ple, squirrel monkeys are used advisor here. The demand for reducing the methods are available which could reduce or in research on malaria and on number of animal experiments has already eliminate the use of animals. Science in gen- sleeping sickness. led to a marked reduction in animal numbers eral has accepted the principle of the three Rs in this area. Alternative procedures for test- (reduction, refinement, replacement). ing toxic substances have been developed Experimental animal research is regu- by basic researchers and have made great lated by the Animal Welfare Act and the cor- progress. However, advocacy of the interna- responding rules - to an extent hardly seen in tional acceptance of these methods and their other areas of animal husbandry or use. Re- validation with accepted procedures is not search with experimental animals is accom- only a matter of science, but mainly of poli- panied and monitored by the Animal Protec- tics and society. tion Committee, animal safety officers and Numerous scientific insights have been veterinary offices. Approval or rejection of won with the help of animal experiments. The animal experiments is accompanied by eth- methods used by researchers to approach bio- ical consideration. This attempts to consider medical principles do not only include studies both the animals’ concerns and the solidarity on the whole organism - the classical animal principle - the moral responsibility of humans experiment - but also studies on lower organ- for each other. 3

39 Senate Commission

The DFG Senate Commission on Animal Protection and Experimentation

t is a central concern of the Senate Com- perts in bodies dealing with animal protec- mission on Animal Protection and Experi- tion and research with experimental animals. Imentation to issue comments on themes re- These include the Animal Protection Com- lated to the use of animals in scientific work mittee of the Federal Ministry of Food, Ag- and to fulfil the commission of the DFG to ad- riculture and Consumer Protection, the Na- vise and inform politicians and the public on tional Ethics Council, the European Science themes relevant to research. In recent years, Foundation and the Board of Trustees of the the Commission has followed the changes in Foundation for the Promotion of Research on national and international law and accom- Replacement and Complementary Methods panied their implementation in Germany. to Reduce Animal Testing. Members of the Commission are active as ex-

Members of the Senate Commission:

Prof. Ulf Eysel MD Prof. Dr. rer. nat. Stefan Treue Institute for Physiology, Department of German Primate Centre Neurophysiology, Ruhr University, Bochum Prof. Hermann Wagner PhD Prof. Axel Haverich, MD Institute for Biology II, Animal Physiology Department of Chest and Cardiovascular and Zoology, RWTH Aachen Surgery, Medical School, Hanover University Prof. Eckhard Wolf DMedVet Prof. Gerhard Heldmaier PhD, Department of Molecular Animal Breeding (Chairman) and Biotechnology, Faculty of Biology – Animal Physiology Gene Centre, Marburg University Munich University

Prof. Bernd Hoffmann DMedVet Prof. Franziska WollnikPhD Department of Obstetrics, Gynaecology and Biology Institute Andrology, Giessen University Department of Animal Physiology Stuttgart University Prof. Wolfgang Löwer DCL, Department of Public Law Bonn University

40 Source of illustrations: A. Anders, Department of Genetics, Justus Liebig University Giessen: 17 Department of Biological Cybernetics and Theoretical Biology, Bielefeld University: 34 German Albert Schweitzer Centre, Frankfurt a. M. (Archive and Museum): 27 Faculty of Biology Animal Physiology, Philipps University Marburg: 19 upper, 33 lower, 37 Faculty of Biology/Neurophysiology, Philipps University Marburg: 33 upper Helmholtz Centre for Infection Research (former: German Research Center for Biotechnology), Brunswick: 21 Institute of Plant Genetics and Crop Plant Research, Gatersleben: 16 Department of Obstetrics, Gynaecology and Andrology, Justus Liebig University Giessen: 19 lower Department of Chest and Cardiovascular Surgery, Medical School: 13, 15, 32, 36 Kunsthistorisches Museum Vienna: 28 upper Mauritius, Die Bildagentur GmbH: Title photo, 5, 12, 22, 23, 35 Max Planck Society, Press Office Archive, Munich: 9 Max Planck Institute for Psychiatry, Munich: 11 Mitteilungen aus den Grenzgebieten der Medizin und Chirurgie [Reports from Areas Bordering on Medicine and Surgery], Vol. 14, Jena 1904: 26 Paul Ehrlich Institute, Langen: 24, 39 City and University Library, Frankfurt a. M./Arthur Schopenhauer Archive: 28 lower ISBN 978-3-932306-87-7