ave S The Primates
A study of the use of primates in experiments ● ● ● ●
Where they come from Life and death in a typical laboratory The experiments The alternatives
All primate species are intelligent, some use tools, others show self-awareness and all are good at problem-solving. Most live in family groups, in organised social structures. We are primates.
Snatched from the wild
In order to distance ourselves from our closest relatives, we refer to them as the “non-human primates”, which helps us to justify their use in laboratory experiments. Yet our primate cousins have proved themselves capable of learning rudimentary arithmetic; they have demonstrated reasoning; some can speak in human sign language. They also display similar emotions to us, such as affection, anger and sorrow – even empathy.
However to argue that our similarities justify their use in laboratories is to ignore at our peril the fundamental differences at the cellular, genetic and immune system level – differences which are so important to experimental results. Humans share more than 90% of our DNA with most nonhuman primates, but nature shows us what a difference this small percentage can make. However, whilst our fellow primates differ in their reactions to chemicals and drugs, we are similar enough to comprehend their suffering.
When they are snatched from the wild, caged, confined, transported; restrained, injected with drugs, force-fed chemicals, deliberately brain damaged - we know they suffer.
Yet despite this, and that more sophisticated alternatives to the use of primates are available than ever before, the numbers being used around the world is rising. Over 10,000 primates will die in European laboratories this year.
Introduction
A third of primate species are threatened with extinction. As governments in primate home ranges make desperate efforts to prevent the poor and hungry eating some species to oblivion, the western research community demands the right to take these species for unnecessary and unreliable experiments, when alternatives are available. In the South American forests trappers hunt for owl monkeys, to sell for malaria experiments in Colombia. The frightened monkeys are torn from the trees, their freedom, and families. Their forest is replaced by the barren factory-type conditions of a laboratory; some are isolated – torture for a monkey. The unethical and short-sighted nature of snatching animals from the wild, as well as the suffering it causes, was acknowledged in EU Directive 86/609/EEC on animal experiments, over twenty years ago. Nevertheless, an estimated 10% of primates in EU labs still come from the wild. Good intent has not been enough. A clear end to this trade is needed. We welcome the fact that the European Commission, in their new proposed Directive to replace 86/609, initially laid out a clear policy that animals from the wild should not be used in laboratories. However these good intentions have been fatally weakened, by allowing unjustified and species “exceptions” to the rule. This is unacceptable.
It is of concern that up to now, the scientific debate on the use of primates in research has been defensive, generalised and dominated by inadequate evaluation and support for scientifically advanced replacement techniques. Europe must establish a clear policy to end the use of apes and wild-caught primates, with a phase-out of all primate use, setting a standard for the world to follow.
The monkey suppliers The journeys that monkeys endure before they reach European laboratories or holding centres are extremely long and frequently mean the animals are confined in transport crates for 30 hours at a time. Left: A monkey peers from a small cage at lab monkey supplier Nafovanny in Vietnam.
modern standards of accommodation and care on a foreign supplier.
Whether wild-caught or captive-bred, the majority of monkeys used in Europe are imported from China, Philippines, Vietnam, Indonesia, Mauritius, Kenya, Israel and Guyana. The monkeys endure long, arduous journeys, isolated, trapped in small boxes, fearful. The cynomolgus macaque, the most commonly used species of lab monkey in Europe, has been described as the macaque species least able to respond satisfactorily to transport.
Supply facilities in Europe are mainly holding centres for monkeys who come from thousands of miles away. For example, the Noveprim facility in Spain is a doorway to Europe for monkeys from Mauritius, where the supplier is known to supplement its breeding stock with wild-caught animals.
Indeed, the vast majority of primates feeding Europe’s laboratories are offspring born of wild-caught parents (referred to as “F1”). Only the prohibition of the F1 animals will put pressure on suppliers not to regard the world’s wild monkeys as their own resource to harvest. The seven year phase out of the use of F1 primates in Europe in the proposed Directive to replace 86/609 must be fully implemented without loopholes; it would be preferable for this to be brought forward. In addition to the long journeys, consideration should be given to the standards of care and accommodation for these animals at the supply source, and whether it is possible to impose
Chimpanzees are so close to us genetically that some scientists have suggested they be reclassified alongside humans. However comparisons of genes and immune systems has shown that this close family connection is not close enough for us to rely on the results of chimpanzee experiments for human safety. The US rushed to use chimpanzees for AIDS research in the 1980s; it was unsuccessful, research followed a different course. This left a huge financial burden and a chimpanzee welfare crisis. The world has steadily abandoned the use of apes in laboratories; in the UK and elsewhere, use of apes has been banned for many years and currently no apes are used in Europe. This leaves only the USA with apes in laboratories. In 2007 the US NIH ended the breeding of chimpanzees for research.
For example, Nafovanny in Vietnam is a huge exporter of monkeys to Europe and the USA. It is, of course, well outside the jurisdiction of the European Parliament or Member States. Behind an initially smart exterior and whitewashed office buildings, in 2008 ADI found monkeys in small wire mesh pens with concrete floors and little enrichment. This would fall well below modern zoo standards.
At the rear of the facility, monkeys were kept alone, in rusty cages under a metre tall - the animals could barely stand up. Some cages were in a state of collapse – leaning at uncomfortable, extreme angles. Yet this facility is approved by the UK’s Home Office as an official laboratory monkey supplier. Nafovanny, Vietnam: Small rusting cages have fallen over - with monkeys living inside them.
The UK’s Animal Procedures Committee has concluded: “The inspectorate has no jurisdiction outside the UK, and therefore, where animals are supplied from outside the UK, any site visits by the Inspectorate depends In its new Directive on animal research, the on negotiation and European Commission proposed an end to cooperation”. apes in laboratories, but this has been eroded by an “exception”. Those with a In 2005 the UK’s vested interest have argued that they may Home Office stated want to use apes in the future, citing for “before primates can example, preservation of endangered be acquired from an species. overseas breeding This is a specious argument, it centre it is necessary is not practical, nor is it a for the Home Office to scientifically sound concept. have appraised and There would be no point of accepted the use of comparison for that centre in order to laboratory apes; ensure compliance conservation takes place in with the section of the the environment, and the Home Office Code of main threats to Practice for the Housing and Care of endangered apes Animals in designated come from human activity. Breeding and
Apes in experiments
Supplying Establishments (1995 HC 125) pertaining to the import of primates” , and: “In effect we will only allow the use of animals from overseas centres we believe produce purposebred animals to acceptable welfare standards”. In March 2005 an inspection of the Nafovanny facility in Long Thanh identified, “shortcomings in animal accommodation and care” and the centre was notified that its “status as an approved centre would cease” once all existing orders for primates had been filled. By the end of 2005 however, the Home Office had received “reassurances and evidence that significant improvements had been made”, and concluded that Nafovanny could meet the required standard. Permission was given for them to continue to supply to the UK. The evidence upon which this decision was based, was “unedited video footage, photographs and reports”. The evidence of our 2008 inspection of Nafovanny would indicate that assertions of government control over standards of welfare at foreign suppliers are more of a public relations exercise, than enforcement of measures to uphold scientific standards and animal welfare.
In the year up to June 2008, at least 476 monkeys were supplied by Nafovanny in Vietnam to Huntingdon Life Sciences (HLS) in the UK.
The monkeys were flown from Ho Chi Minh to France and then taken by road to England. HLS understood the journey to take about 30 hours. On arrival most monkeys were frightened and hid at the back of the box; injuries from the journey included abrasions to heads and faces.
Group housing in the stock unit of HLS. This is as good as it gets for the monkeys who will be transferred to another unit (right and below) for experimentation. It looks like an impoverished, unregulated zoo, yet these monkeys will be used for products for multi-billion Euro clients by a company that has announced annual sales of €137million with profits of €31.5million.
scrutinised in advance by regulators. The reports of the tests are the property of the customer. Such experiments are rarely, if ever, published.
Between 2006 and 2008 an ADI/NAVS investigator studied the use of primates at HLS, which has a capacity for around 500 macaque monkeys. This study provides a rare insight into how these monkeys live and die behind closed doors. On arrival monkeys are placed in a stock colony, with up to fifteen animals in a room little more than two metres wide and tall by three metres long, with a small catching cage, 1 metre by 2 metres tall. There is no natural light. These wild animals would normally live in trees, in large troops of fifty to one hundred monkeys, and might range over 1.5 kilometres in a day. Their HLS home provides an average of one cubic metre per animal.
The monkeys are moved to Unit M12 for experimentation. Some are now confined in cages of roughly one cubic metre. Three of these cages may be linked, with three monkeys sharing the space. Their rich natural habitat now replaced by a single horizontal bar in each cage.
These are the conditions provided by European and UK regulation for over twenty years, where it is acknowledged that, “Primates have high intelligence, most have arboreal habits and all need complex, stimulating environments.” The failure of these regulations to uphold standards, and the gulf between how welfare is perceived inside and outside of laboratories, is apparent from our photographs.
Primate experiments Experiments on primates effectively fall into two broad groups: academic research which is varied, and regulatory testing – required for products to be sold on the market – which are standardised. Most of the monkeys arriving in European laboratories are used in the type of regulatory testing that is carried out at Huntingdon Life Sciences (or HLS).
It would be difficult to describe the housing at HLS as anything more than the bare minimum. This is a wealthy company, providing a service to multi-billion pound/euro companies, yet these highly intelligent animals are provided with just enough to sustain them before they suffer in tests for products. A monkey was discovered with blood on its face and the ends of the animal’s toes were missing. Some staff suggested that the monkey had chewed off its own toes, however our investigator noted that the wounds were clean straight cuts, and concluded that the animal was more likely to have trapped its foot in some part of the cage, sliced its toes off trying to free itself and then put its foot in its mouth. Missing digits were not considered to be an uncommon occurrence.
One of Europe’s largest commercial animal testing facilities, HLS is contracted by pharmaceutical, chemical, industrial and other companies to perform toxicology (safety/effects testing) and other tests on their products. This is one of the most secretive areas of animal experimentation. Permits for regulatory tests are granted in ‘groups’ and therefore individual sets of experiments are not
A barren metal box replaces a stimulating habitat among the trees for this monkey. Government regulations have failed to deliver the welfare standards the public expects.
Above: A monkey huddles in a cage, the mesh floor designed to collect urine for testing. Right: Monkeys are severely restrained for experiments. For some the stress is so great that they suffer rectal prolapse.
Monkeys had a range of cuts and injuries from the cages, with several requiring veterinary attention. Scrapes and scratches from being removed from cages; a chain being used to secure a cage pierced the cheek of a female, leaving her unable to eat and having to be force fed each day. Others suffered diarrhoea, nose bleeds, or ate and then vomited their own excrement. Tests we observed used anything from 4 to 72 monkeys and all involved the physical restraint of the monkeys, which clearly caused them distress.
It takes three people to dose a small monkey by mouth. The “catcher” pins the animal’s arms, the “legger” takes the legs, and another feeds a rubber tube down the throat to the animal’s stomach and pumps in the test substance. In other tests the monkeys are strapped down in chairs. For some the stress is so great that they suffer rectal prolapse, which is a known indicator of stress in restrained primates. During the study of an incontinence drug, three of the monkeys being restrained suffered rectal prolapses, and one being used to test a drug suffered repeated prolapses.
During an oral dosing study, several monkeys suffered from vomiting and salivation on numerous occasions. Several produced black-stained urine on their cage floor. One almost chewed off its whole finger and continued to chew its hand after the vet had dressed it. Others showed a range of symptoms such as tugging at chest skin, pushing their fists into their mouths, trying to bite through the metal food hopper, pushing large amounts of sawdust into cheek pouches, chewing metal and dragging teeth along the bars of the cage. Five days later, some showed signs of twitchy feet, indicating a kind of pins and needles sensation. Several animals were clearly distressed, yet they were orally dosed as normal and returned to their cages. At around the same time, a study of the same product was started in rats and researchers had noticed the rats chewing their feet and eating sawdust. Almost chewing off a finger is a substantial clinical sign, so as a result the dose for one group was lowered.
This demonstrates how predictions of likely severity can be misjudged. The new European Directive needs to include a new system to report upon unexpected levels of suffering or other events, in order for improvements in protection of animals. An inhalation study provided another example of how the severity of a procedure can be misjudged:
The full report Primate Testing and the DVD Save the Primates which feature the investigations reported on here are available from ADI.
Over a period of time three monkeys on an inhalation study died or had to be killed due to partially collapsed and blocked lungs. Three other animals also collapsed but were revived. After death, it was found that these animals had blackened lungs. Clearly they would have suffered a great deal.
An additional fear and stress for laboratory monkeys is that they have the ability to anticipate what is going to happen to them. In the wild, these monkeys are intelligent, they innovate, learn from each other and pass on skills such as cleaning food or fishing. Yet at HLS caged monkeys were able to see other monkeys being strapped down and experimented upon. Some monkeys had an incontinence drug pumped into their stomach every day for a year. Others were bled multiple times in a day, or day after day – enduring over eighty bleeds. The ADI/NAVS investigator reported that on the days when the animals were killed and their bodies studied, the other monkeys would fall silent. Stress and anticipation are both known to affect the outcomes of experiments and distort results.
Documents leaked from another contract testing laboratory, Inveresk in Scotland (ADI/NAVS report, 2005), show that during tests for an asthma drug, monkeys suffered with liquid faeces; redness of face, lips, feet and hands; swollen penises and scrota; a loss of body tone; low heart rate; hernias; they had body tremors and a quiet, hunched appearance.
There is an opportunity to end this suffering and improve science – governments must not waste it.
Monkeys are able to watch from their cages (in the background) as other monkeys are strapped down and experimented upon.
Replacing primates
Advances in science and technology provide non-animal techniques that are faster, more accurate and of direct relevance to people.
If the EU and Member States are to take serious steps to replace animal tests with advanced technology, then it is vital that the animal tests be ended earlier in the programme – to be replaced by advanced methods based upon human data, such as microdosing. Industry and regulators, and indeed much of academia, are inherently resistant to change, but the reality is that primates are a poor predictor of human responses.
There are now a range of multidisciplinary, sophisticated techniques that allow the safe and accurate examination of potential effects on humans (see list). We have seen how implementation of the Cosmetics Directive has ensured the validation and implementation of replacements for a range of tests, and as a result, how it has dramatically Microdosing in combination with Accelerator Mass Spectrometry provides a way of safely assessing cut animal use.
new drugs in humans.
Animal research on the other hand, is outdated and suffers from the flaw that all species respond differently to substances. Studies have shown differences between humans and laboratory monkeys, on average, a third of the time.
This was illustrated when the UK test drug TGN1412 caused terrible, almost fatal, and permanent side effects in human volunteers. Yet the drug had been given to laboratory monkeys in doses 500 times that given to the volunteers, without side effects. Now many agree that this disaster could have been avoided by using advanced technology – microdosing.
Replacing primates in commercial testing
Microdosing involves giving tiny, safe, doses of new compounds to human volunteers and samples of blood or urine can then be analysed by Accelerator Mass Spectrometry (AMS). AMS counts individual atoms – it can detect a liquid compound even if just one litre of it has been diluted in the ocean. AMS can show how compounds have been absorbed, distributed, metabolised and excreted by the human body. The EU Microdose AMS Partnership Programme recently compared microdosing data to animal tests. It proved to be 80% predictive of human drug absorption and distribution – significantly more accurate than primate, dog and rodent models.
Adoption of high-level advanced techniques such as microdosing/AMS would allow drug development to be accelerated, accuracy to be improved, and costs cut.
Whilst regulatory testing is the largest area of primate use in labortories, it is one section of the overall testing strategy for new drugs. Therefore primates could be replaced more easily than was the case for the EU cosmetics testing ban, which was more complex because it needed a ‘start to finish’ replacement strategy. Primates come at the end of the regulatory testing strategy, along with dogs. They fulfil the requirement for tests on a second mammal, apart from a rodent. This means that by the time the monkeys were being strapped into restraint chairs for the experiments we have described overleaf, hundreds even thousands, of smaller animals would already have died to test the same product.
Implementation of replacements for primates could signal the start of an evolution throughout regulatory testing, towards modern methods. Such advanced techniques are good for European science and industry, good for animals, good for people.
Replacing primates in academia
Academic experiments in universities, particulalrly neurological research, is another large area of primate use. These studies cause extreme suffering and can include implanting electrodes and other equipment into the animals’ heads. Often this socalled ‘fundamental’ research does not describe any potential application for human benefit.
Yet, advances in modern scanning techniques such as fMRI and MEG are enabling non-invasive neuroimaging of the human brain, providing unprecedented understanding of mental illness, neurodegenerative diseases, vision, hearing, speech, pain and more. This provides data of direct relevance to patients, who can be asked to describe how they feel. In 2008, a meeting at the European Parliament was presented with a comparison of data from scanning studies of human patients and electrodes implanted in the heads of monkeys. The same level of data was obtained – yet importantly one set of data was of direct relevance to people.
There are no regulatory requirements for these academic experiments, so this is a field where replacement could be very rapid. A different approach would be needed for different fields of research, but this could be achieved through expert consultation and a focussed, technical review, managed by the Commission, under the new Directive.
The latest scanning techniques can enable direct study of the human brain instead of invasive experiments on monkeys.
Alternatives The benefits of some of these new techniques is that they can build on and advance existing knowledge, rather than simply starting from scratch in a different species. Here are some examples of modern techniques that can save primates, advance human health, and put Europe at the forefront of science.
Microdosing and Accelerator Mass Spectrometry (AMS): Giving safe ultra low doses to volunteers combined with precision analysis (see Replacing Primates).
recreate whole body systems, such as the artificial immune system.
Biochips: These show the effect on different cells in the body and how toxicity is altered when the compound is broken down (metabolized) in the human body. They provide data quickly and cheaply, including data for different human organs.
Toxicogenomics: This seeks to translate data about genetic variation and gene expression into an understanding of the biological systems in organisms, including humans, and the effects of changes in the systems on health.
Post mortem analysis of tissues donated by patients to allow cellular examination of human disease.
Computer analysis, simulation, modelling and more: For example QSARs Advanced scanning techniques such as MEG and fMRI for (Quantitative Structure Activity detailed study of patients (see Replacing primates). Relationships) – a computer modelling system, which correlates a compounds’ structure and properties with its activity; Derek for windows (DfW) is an expert knowledge base computer programme that applies Modern research takes place at the genetic and cellular rules; it predicts a chemical’s toxicity level, where new technology allows greater precision than from its molecular structure; and High ever before. The fundamental flaw of animal research (an throughput screening: This involves idea now over one hundred years old), is that each robotics and sophisticated control species responds differently to chemicals, drugs or other software which rapidly analyses products. This is because of the biological and genetic compounds for drug discovery. differences between species. It means that we cannot rely Human cell cultures: upon the outcome of animal tests. For example: growing human cells ● Non-human primates are distinct from us in the way they in the laboratory, so express genes in the brain, with even major differences that they reflect how between ourselves and chimpanzees. they work in the body, and how they respond ● Human brains have a folded cerebral cortex (a gyrencephalic brain) whereas smaller to test compounds. primates, such as the marmoset, have a smooth cerebral cortex (a lissencephalic brain). There Specialised cell are anatomical differences between these and evidence suggests functional differences, too. cultures, such as liver, ● Lower and higher primates differ from one another by a number of structural features in their kidney and brain cells nervous systems and sense organs. are being used. ● The role of the hippocampus in human memory was complicated by findings from monkeys Human tissue cultures: and other animals, until its role was established in 1986 from human study. Pharmaceutical companies already use ● Gout is caused by excess uric acid, which is produced in monkeys, apes and humans, but liver tissue to provide biological data and only humans get gout. safety test compounds, because this avoids the problem that animal test data ● HIV can infect chimpanzees and rabbits, but does not induce disease. Human beings are the is not a reliable indicator of likely effects only species to have been found to be susceptible to HIV. in humans. (It is only government ● The way drugs break down and are excreted are similar in monkeys and humans, but regulations that require use of animals in metabolism rates differ radically. order for a product to be approved for sale). ● The drug chloramphenicol does not have the adverse effect in monkeys and dogs that has
some primate species differences
3-dimensional (3D) human tissue engineering can be used for drug testing. The scaffold can be made from synthetic or natural materials, with differing scientific advantages. Tissue can be constructed to
occured in humans.
Herpes B virus in monkeys may cause lesions on the face, lips, mouth and body, but they can carry the virus without suffering the disease. In humans, the disease is rare, but almost always fatal.
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● The drug azauracil caused no apparent toxic effects in monkeys; in humans, it produced such unpleasant side effects that it had to be taken out of use. ● Aspirin causes birth defects in monkeys, but has been widely used by pregnant women and has not been shown to produce any kind of malformation.
The European Commission has proposed a new Directive to replace the 22-year-old EC Directive 86/609/EC governing the use of animals in research. The new directive is to be discussed in the European Parliament’s Agriculture and Rural Development Committee in early 2009. It will then go before the full Parliament, followed by the Council of Ministers. This is the first major revision in over 20 years and provides an important opportunity to advance animal protection and European science.
The Revision of EC Directive 86/609
In 2007 a group of respected MEPs, Jens HOLM (Sweden, European United Left), Rebecca HARMS (Germany, Greens), John BOWIS (UK, former Health Minister, European People’s Party), Martine ROURE (France, VP of EP, Party of European Socialists) and Mojca DRCAR MURKO (Slovenia, Alliance of Liberals and Democrats for Europe) tabled Written Declaration 40/2007. 433 Members of the European Parliament (55%) signed, and every Member State and political persuasion was represented, including many prominent Europeans: Michel ROCARD, former French Prime Minister; Anneli JÄÄTTEENMÄKI, former Finnish Prime Minister; Luigi COCILOVO, Gerard ONESTA, Edward McMILLAN-SCOTT, Miguel Angel MARTINEZ MARTINEZ, Mechtild ROTHE and Luisa MORGANTINI, Vice-Presidents of the European Parliament; Joseph DAUL, President of the EPP-ED Group; Monica FRASSONI, co-President of the Green/EFA Group; Francis WURTZ, President of the GUE/NGL Group; Cristiana MUSCARDINI, coPresident of the UEN Group; Linda McAVAN and Pasqualina NAPOLETANO, Vice-Presidents of the PES Group.
Written Declaration 40/2007
Written Declaration 40/2007 urges the Commission, the Council of Ministers and the European Parliament to use the revision process of Directive 86/609/EC as an opportunity to: (a) make ending the use of apes and wild-caught monkeys in scientific experiments an urgent priority, (b) establish a timetable for replacing the use of all primates in scientific experiments with alternatives. Although the Declaration took a cautious approach to outlining exactly how primates should be replaced, it is widely acknowledged that for the Cosmetics Directive and action on CO2 emissions, it proved necessary to set targets in order to achieve the objectives. It is of great concern that the Commission has chosen to ignore such a mandate, which is backed by 80% of European citizens who, in a Commission survey, said that they felt that primate experiments were “not acceptable”.
The proposed Directive does not phase out a single primate experiment. There is no mechanism that would establish a formal review process which could consult, investigate and set timetables for the replacement of primates. Several well intentioned Articles are undermined by loopholes: A ban on the use of great apes in experiments is undermined by spurious “exceptions”. A ban on the use of wild-caught monkeys and the phase out of F1 monkeys (those born of wild caught parents) both allow for unjustified “exceptions”.
The Commission Proposals on Primates
The following would achieve the goals of Written Declaration 40/2007 and meet with public and European Parliament approval: ● A prohibition on the use of great apes (without exceptions). ● A prohibition on the use of wild-caught monkeys (without exceptions). ● Full implementation of a phase out of F1 monkeys (offspring of wild-caught parents) (although we favour earlier than the 7 years phase-out suggested in the draft). ● Arrangements to replace the use of primates to be established during bi-annual, thematic reviews setting timetables or objectives for replacement in specific areas.
Proposals to Save Primates
Proposals to protect all animals: ● Bi-annual reviews of the use of animals in specific tests, implementation of advanced replacements and other key issues – review every twenty years is too long – it means that the legislation does not keep up with developments in science and technology. ● Improved transparency and public and scientific scrutiny of experiments. ● Improved regulatory testing scrutiny by governments. ● Compulsory data sharing to prevent duplication (as already implemented under REACH). ● Retrospective review of experiments so that the actual impacts of the experiments are judged, and any unforeseen suffering is reported. ● Independent ethical, scientific and replacement review of proposals to use animals - before authorisation is given.
Animal Defenders International ● National Anti-Vivisection Society ● Lord Dowding Fund for Humane Research Millbank Tower, Millbank, LONDON, SW1P 4QP, UK. Tel: +44 (0)20 7630 3340 Fax: +44 (0)20 7828 2179 e-mail: info@ad-international.org www.ad-international.org • www.navs.org.uk • www.ldf.org.uk
www.savetheprimates.org