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"Mad Cow" Disease : 85 questions English version In relashionship with the exhibit "When cows go mad" Updated: July 12, 2001 This document looks at the main aspects of the Mad Cow disease and its consequences on public health. It is organized around 85 questions, organized in ten themes. Find out more on Cité des Sciences website www.cite-sciences.fr/vachefolle Mad Cow" Disease : 85 questions 1. BSE, "Mad Cow" Disease 2. BSE throughout the world 3. Prions 4. Transmission channels 5. Meat and bone meal 6. The new variant of the Creutzfeldt-Jakob Disease 7. Public health protective measures 8. BSE screening tests Testing launched in France in 2000 Tests carried out in Europe in 2001 Other questions on the screening test 9. Sheep and other animal species 10. What we have (temporarily) learned from the crisis Scientific advisor: Dominique Dormont. Texts: Philippe Dorison. Translation: Timothy Fox. Senior editor: Alain Labouze. English document on Mad Cow desease Page 1 1. BSE, "MAD COW" DISEASE How to recognise BSE? The clinical diagnosis established by veterinarians takes into account numerous possible symptoms, including a certain anxiety or aggressiveness by the animal and often an exaggerated sensitivity to light and sound stimulation. Motor disturbances can also appear, such as hypermetria where the animal has a tendency to take very large strides like a horse. In certain cases the symptoms can regress or even disappear in the disease's final phases. Generally speaking, clinical diagnosis of BSE is difficult, for the symptoms and in particular their sequence can vary widely from one animal to the next. It is only a hypothesis, but to explain this variability we surmise that the order in which the regions of the brain are afflicted is not always the same. The formal diagnosis is established only after the animal's death by studying samples taken from the brain. The disease appears on average five years after infection, and death occurs within a few weeks. Where does BSE come from? No one knows for certain. One theory has it that scrapie in sheep jumped the species barrier and was passed on to cattle. It was the most widely held theory at the end of the 80s, but it has not yet been proven. Another theory has it that BSE has always existed in a sporadic and very rare manner and that it degenerated into an epizooty (an epidemic among animals) through the recycling of infected corpses (or even a single carcass!) via meat and bone meal. Indeed, one-off cases of diseases similar to BSE have already been observed in the past, in particular a case in south-western France that gave rise to an article in a veterinary journal in 1883. How has it become an epizooty? Through the use of meat and bone meal. In this sense it makes no difference if the disease originated among sheep or cattle. The changes in the production method of this meal in Great Britain in 1980 most certainly played a part in the process. Designed to lower production costs and improve the quality of protein, the new process went with a lowering of the processing temperature that probably made it possible for the infecting agent to develop more widely. But the conclusions of the Phillips report in 1999 implied that even without this change in production methods, the disease might have spread. Another important cause of the explosion of this disease comes from the very principle of the industrial production of the bone meal. It introduces blending on a large scale, also known as ìpoolingî. Thus a small quantity of infected matter manages to spread in large volumes. These ìpoolingî techniques had already been questioned in the French affairs of contaminated blood and growth hormones. How did the disease spread in France? It happened in two phases. The first French animals infected were probably contaminated by British meal, which corresponds to the very first cases to appear between '91 and '95. This contamination should have stopped with the animals born at the end of '89 when the import of British bone meal was prohibited. But we can only suppose that illegal importing continued and that it prolonged this first wave. After that, it is very likely that the carcasses of French animals afflicted with BSE were recycled in the production of French bone meal, thereby provoking the second wave of English document on Mad Cow desease Page 2 the disease in France. The risk was probably increased by the fact that, at that time, the specified matter at risk was not withdrawn from the bone meal production circuit. In the first part of the 90s, BSE seemed a uniquely British problem that affected France in a purely anecdotal way. Despite the founding in ë90 of a network of passive monitoring by veterinary health officials, the disease was generally little known and perhaps wasnít taken seriously enough. Diseased animals might have gone unnoticed and thereby contributed to the spread of the epizooty. English document on Mad Cow desease Page 3 2. BSE THROUGHOUT THE WORLD How extensive is it in France? Charts show that it is still expanding and that it has not yet reached its maximum spread. As of May 2001, 315 cases have been counted. 74 of these were detected by tests done before any symptoms appeared, and 19 by systematic testing of cows over 30 months old. Yet it is possible that some cases slipped through unseen, especially in the first half of the 90s. How extensive is it in Europe? The United Kingdom is obviously the hardest hit with more than 180,000 cases since ë85. This accounts for more than 99% of the cases in Europe. Most other European countries have been affected, in particular France, Ireland, Switzerland and Portugal. Up to the end of 2000 the only two countries to have started active detection campaigns with rapid tests were Switzerland and France, which tends to increase the number of reported cases. But by the beginning of 2001, tests are being run throughout Europe, and cases have appeared in Austria, Belgium, Germany, Italy and Spain. Some time will therefore be required before knowing the real incidence of the disease in all of Europe. Only northern Europe (i.e. Sweden and Norway) seems spared so far, but even there nothing can be confirmed before many studies are carried out. How widespread is it in the world? The disease is apparently limited to Europe, but it would be foolhardy to claim this with any certainty. Indeed, English, German and French cattle and feed have been exported to numerous countries, and as yet no countries outside of Europe seem to have equipped themselves with comparable monitoring means. Have any countries been spared BSE? In Europe, probably not. In the rest of the world perhaps certain countries like New Zealand, but we have to be very careful in claiming this. In the United States for example, encephalopathies would now appear to be found in wild animals in fairly large numbers. The American health authorities have done a few tests to prove that there is no BSE in America. But the methods they have used would probably not have found even the cases that were discovered in England in the mid 80s! The risk of seeing BSE appear in North America is not negligible. Indeed scrapie exists in the United States, and the changes in the production procedures of the British feed incriminated for the part it played in the explosion of the epizooty came from an American patent. Why would some countries try to hide BSE? It is only too clear that the presence of BSE in a country is very bad news for business, especially for exporters of meat and cattle by-products. Amongst these by-products, fetal bovine serum is particularly important. It is heavily used in the pharmaceutical industry, namely for vaccines and biotechnologies. It hasnít been proven that a sick cow transmits the infection to this product, but, as a precaution, only countries believed to be BSE-free are allowed to sell it. This is namely New Zealand, Australia, Canada, and the USA. English document on Mad Cow desease Page 4 3. PRIONS What is a prion? It is a protein that lives on the surface of cells and whose role - probably linked to cell communication - is not very well known. In a healthy organism, this protein is easily eliminated. But in sick people it becomes very resistant and is no longer destroyed by the enzymes which normally ìrecycleî it. It aggregates into clusters of 10,000 to 100,000 units which then kill the neurones. The word ìprionî (pronounced ìpree-onî) is derived from the abbreviation of ìproteinaceous infectious particlesî. The size of prions makes direct observation practically impossible. To date, only the crystal structure of a yeast prion (very different from the mammal prions that cause the TSSEs) has been observed in a cyclotron (a particle accelerator). Are prions a cause or a consequence of the disease? There are several theories, but the one of the American Stanley Prusiner, who won the 1997 Nobel Prize for his work, is the most widely accepted today. It sees the pathological prion as the infectious agent: this protein alone would be the cause of the disease with no need of a virus or any another micro-organism. This approach is very radical, for it goes against everything that has been known till now in biology. This model is globally accepted, but there is no definitive proof to support it. Some research teams continue to think that there is another infectious agent not yet discovered, and that the prion is merely a tracer of the disease. The majority of the scientific community does not share this hypothesis, since todayís biological techniques are considered to be very effective in detecting viruses whenever they are present. How does a prion become pathological? We donít really know. The difference between a normal prion and a pathological one most probably has something to do with their 3D shape, i.e. the way in which the amino acids that make them up (and which are exactly the same for the two prions) are folded in space. It would appear that a badly shaped prion may be able to transmit this defect to other, healthy prions, making them change shape. But details of the reaction, transconformation, remain obscure. It is supposed that other elements take part in this mechanism, though itís not known which ones. How do pathological prions get to the central nervous system? The path taken by the infectious agents for reaching the brain has not been completely worked out, and describing it is still partly in the realm of hypothesis. At first the infectious particles enter the digestive tube. As the pathological proteins become resistant and aggregate into clusters, they cannot be destroyed during digestion as healthy proteins would be. It is believed that these proteins ìreplicateî in the lymph tissue linked to the digestive tube, i.e. they spread the infection there and transform healthy proteins into pathological prions. These mutated proteins then follow the nerves up to the central nervous system where the infection continues to spread, causing the death of the neurones. Is the 3D structure of the human prion known? The normal prion protein structure has been known since 1996 and is composed of three helixes. But the shape of the pathological prion is not known for sure. It is assumed that at least one of the helixes is replaced by a folded layer. It is also English document on Mad Cow desease Page 5 assumed that there may be several different shapes of pathological protein, which would explain the presence of several ìstrainsî of the Creutzfeldt-Jakob disease. Why bother trying to discover the 3D structure of the pathological prion? It would be a major stride forward for research. By highlighting the abnormal structure, we would have a better idea of the molecular mechanism involved in the shape change. By knowing on what level of the molecule this defective folding takes place, we might even find a way to correct or impede the transconformation. Why are there so few real results in prion research? The pathological shape of the protein is very hard to purify and therefore to study. The size of the infectious agent (at a molecular scale) makes direct observation practically impossible. Studies on animal models are long because of the incubation time. They are made more complex by the fact that many animals have to be infected in order to have only a few develop the disease. Another problem lies in the fact that the infectiousness of the prion requires a lot of experimental precaution. Is there enough money for prion research? The French government has announced plans to triple funds, increasing them from 10.7 to 32 million euros (from 7 to 21 million £) per year as of 2001 - while 76 million euros (50 million £) were collected in the 2000 myopathy-drive. Moreover this research is relatively recent, for prior to 1996, it was not a part of the priority programmes. It is therefore starting up with somewhat of a handicap. In Great Britain the tradition of research on this subject is greater, because sheep scrapie has been around for a very long time. It is also certainly very active in the United States, but with a sizeable part of its funding coming from the private sector, it is hard to assess the amounts allocated to it. English document on Mad Cow desease Page 6 4. TRANSMISSION CHANNELS Are we sure of knowing all channels of transmission? No, nothing is certain in this field. Although bone meal has clearly been identified as the main vector of contamination, responsible for spreading the disease on an industrial scaleî and of the explosion of the epizooty, nothing proves that it is the only thing able to spread the disease. Itís even probable that there are other channels: transmission from mother to calf, infection from the zero-milk replacers or transmission through the blood (something still unconfirmed by epidemiological data). There may well be other channels still completely unknown. They may be related to dissemination of infectious agents in the environment. They are generally referred to as third channel In any case, each time an animal Born After the Ban (BAB) is contaminated, the controversy spurs up: was it due to a fraud, or to a non-identified cause? Does the cow infect her calf? There are cases that would imply that cattle had been contaminated at birth or before. But the small number of cases involved and the present state of research do not make it possible to draw formal conclusions. Moreover, a British study has shown that in the mother final year of incubation, there was a 5% risk of transmission from mother to calf. This transmission does not seem to happen in utero. This question is perhaps more important than it appears: transmission during gestation would imply a risk for the fetal bovine serum, widely used in the pharmaceutical industry. As a precautionary measure, only a few countries, reputed as being totally BSE-free, are authorised to supply this serum. Is blood a contamination vector? Experiments with sheep have shown that BSE can sometimes be transmitted through a complete blood transfusion (one out of nineteen experimentally transfused sheep). These findings open up research avenues more than provide certainties, for todayís techniques arenít able to detect pathological prions in blood, though it can be present in quantities too weak to be measured yet sufficient to transmit the disease. This risk of blood contamination may seem anecdotal for cattle or sheep, since exchanging blood between animals is not likely to occur without human intervention. However, there is still a possibility of transmission of the new variant of the Creutzfeldt-Jakob disease by blood transfusion between humans. This risk, often discussed, is taken very seriously. Can the zero-milk replacers contaminate? These products are used as feed supplements for young cattle when being weaned from their mothers. They have become necessary because of the use of protein supplements in cowsí diets. To meet market demand, animal or plant proteins are given to dairy cows to enable them to produce greater quantities of milk that is richer in protein. But such enriched milk is indigestible for young calves and heifers who get sick if they drink it. As zero-milk replacers are subsidised, it is costlier for a farmer to let a calf suckle its mother, rather than sell her milk and feed the calf with the milk-replacer. This weaning feed is enriched with animal fat. If bovine fat is used, it is not impossible that it be one of the BSE transmission channels. What is meant by a ìthird channelî? English document on Mad Cow desease Page 7 It refers to all the contamination channels as yet unknown. For instance, the infectious agent can be disseminated in the environment, and spread via earth, grass, or even water. At this stage, anything seems possible. On this topic we can refer to the work of Carleton Gajdusek, Nobel Prize-winner in medicine for his work on Kuru. He demonstrated that matter infected by the pathological prion and buried in the soil was still contaminating three years on. All these possible third channels cause people to worry about the storing and destroying of bone meal, and more generally over the processing of waste from the cattle connection. English document on Mad Cow desease Page 8 5. MEAT AND BONE MEAL What is meat and bone meal made of? Meat and Bone Meal (MBM) is derived from slaughterhouse and butchering waste, i.e. animal carcasses (cattle, sheep and others) from which the meat has been taken, offal and secondary products not sold for human consumption. More than half of the animalís weight is often eliminated this way. The waste is crushed and cooked. Most of the water is eliminated, reducing the volume and weight considerably. The powder that is produced is very rich in proteins. Up to the 80s, the process used in Great Britain required a solvent for eliminating fats. To get rid of the solvent, the mixture then had to be heated to a very high temperature. A patent imported from the United States made it possible to by-pass this phase with a result of savings on the solvent, on energy and obtaining better quality protein. But with a subsidiary result of the advent of the BSE epizooty a few years later, very probably amplified by this lower cooking temperature. Under pressure from public authorities, the vast majority of the manufacturers now seem to have come round to the cooking standards decreed by the German industry, i.e. 133∞C under 3 bars of pressure for 20 minutes. Why was animal meal given to cattle? This meal was never the basic feed for cattle. It has only been used in small quantities and blended in with other components called ìnitrogenous correctorsî, to improve cattle-raising profitability. The idea is to increase milk production and to bolster its protein rate. Intensive farming requires cows to produce about twice as much milk as they would naturally. To reach these standards, they would have to eat more grass or forage than their stomachs can handle. At the beginning of the 20th century, a solution was found: cows were given an animal or plant protein supplement. This had the added interest of eliminating cumbersome waste. Originally, this was done to produce enough milk to feed the population. Today, the real problem is over-production, and quotas have been imposed. Protein supplements are now mainly used to increase cattle-raising profitability: an equal amount of milk is being produced with fewer animals. The question is: should we keep this up? Have all cattle eaten meat and bone meal? No, a large part of French herds have probably never eaten MBM. Itís goal being to enhance milk production, the meal was given to milk-producing cows rather than to animals raised for their meat. This is probably why most BSE cases hit dairy cows hardest (93.3%, as opposed to 6.7% of suckling cows). But other factors might also explain the small number of BSE cases in suckling herds, in particular the earlier slaughtering of animals raised for meat. Yet suckling herds are not entirely immune to BSE. Some cattle raisers have seen a case appear in their herd although they were convinced they had never used MBM. This leads to suspicions of accidental blending of feed, frauds, not to mention all the other possibilities of contamination, known or unknown. Since when has meat and bone meal been stigmatised? English document on Mad Cow desease Page 9 Bone meal was prohibited in Great Britain as feed for ruminants in 1988. Amazingly, this highly suspicious bone meal continued to be imported into France for another full year, until the end of 1989. And it was not before 1994 that all animal bone meal, even French, was prohibited for other French ruminants. This bone meal then continued to be produced for other animals (mainly pigs and fowl). It was in 1996 that the risky offal were excluded from this feed. From there on, the two production chains for bone meal have been separate without the possibility of their mixing together. On the one hand, the bone meal for non-ruminant animal feed could not contain specified risk matter, which meant that it was composed only of matter authorised even for human consumption. On the other hand, bone meal produced from butchery waste, including all risk matter, is earmarked to be destroyed. It is only transformed into meal as an intermediary step in its destruction, for this makes it less cumbersome to handle and easier to incinerate. These two production processes must be completely separate and not even exist in the same factory. Moreover, standards have been established for preparing this bone meal, i.e. 133∞C under 3 bars of pressure for 20 minutes. A process that seems sufficient for sterilising matter with mid-level degree of infection. Once all these precautions have been taken, the meal supplied to pigs and fowl is meant to be perfectly safe. It should not even present a danger for cattle if they should ingest small quantities by mistake. Why was a total ban of meat and bone meal imposed at the end of 2000? If all previous measures concerning meat and bone meal had been perfectly applied, this ban would not really be justified. This measure might therefore be taken as a confession of impotence in rendering the use of meat and bone meal safe. A total ban is probably easier to apply and especially to monitor. Another advantage of this measure, supposing it be scrupulously obeyed, is that it would make it possible to check after a few years time if there are not other causes of contamination to be looked for, or if this ban puts an end to the disease’s development. Looking at the vicious circle involved in spreading the disease, one can note that all possible measures to eradicate it had already been implemented. This total ban therefore seemed to be the only possible measure taking the fight against the disease a step further. However, it is very likely that if this measure had been taken some twelve years earlier, it would have gone a long way in preventing the spread of BSE. But it would have cost a lot of money. Would public opinion have accepted that? In any case, it was not accepted by European political leaders. Why was this decision so long in coming? First of all, we might have been faced with the complicated and costly problem of eliminating all meat-processing waste. The sums involved are put at thousands of millions of euros. If these measures have been accepted by governments and public opinion, it is because they appear as an indispensable health precaution. Furthermore, animal meal is a cheap source of protein, which is especially important in low-margin industries such as pig-raising. Eliminating it will necessarily mean a rise in the production costs of certain meats. The free circulation of merchandise in Europe made decision-making more difficult: a country that might have applied such decisions English document on Mad Cow desease Page 10 unilaterally would have prevented its cattle-raisers to compete on equal footing with competitors in other countries. And most of the European countries that thought they were left unscathed by the BSE, in particular Germany, weighed in with all their clout to prevent such measures being taken. Were the many precautionary measures fully implemented? This is the crux of the problem, and we can suppose that their application is often imperfect for several reasons: technical difficulties, fraud, lack of zeal, profitability It is also hard to implement frequent and systematic monitoring to enforce the rules. There are strong suspicions that illegal importation of British bone meal continued after it was prohibited. A judicial inquiry has been opened, but the case seems complex. Likewise, withdrawing risk matter is often easier said than done. For example, it is very hard in abattoirs to completely eliminate the spinal cord, at least as long as the backbone is sectioned down the middle. Also, it has not been proven that the separation of the bone meal production lines was implemented within the set deadlines. Finally, if these regulations were not respected and have led to contamination, it is nearly impossible to establish the fact in hindsight. Tracking the elements contained in animal feed is practically impossible, especially when this means going back four to six years to find out what might have made the cow sick. English document on Mad Cow desease Page 11 6. THE NEW VARIANT OF THE CREUTZFELDT-JAKOB DISEASE What is the Creutzfeldt-Jakob Disease? This disease, first identified in the early 20s, attacks the central nervous system. It is always fatal and can be classified as a TSSE. Just over 1 person out of a million is afflicted with it every year. It exists in three forms. The form known as sporadic is the most frequent: it represents 85 to 90% of all cases. There is no direct cause explaining its appearance, and it generally attacks people over 60. The genetic form is much rarer (10 to 15% of cases) and is explained by a mutation in the gene coding for the normal prion protein. The iatrogenic form is due to contamination through a surgical or medical act. The best known example, especially in France, is the contamination by the so-called extractive growth hormone in which 76 people developed the disease. For a while, this hormone was obtained from the brains of dead people, certain of whom, it turned out, were carriers of the agent of the Creutzfeldt-Jakob disease. Since then, itís become possible to produce this hormone through genetic engineering. What is the new variant of the Creutzfeldt-Jakob disease? This disease bears close resemblance to the Creutzfeldt-Jakob disease, but it differs enough on a certain number of points to classify it as a new disease. First of all, it is likely to affect much younger people, sometimes even teenagers, and it lasts longer. The infection spreads to more parts of the body (tonsils, appendixÖ) than with the Creutzfeldt-Jakob disease, where it remains confined to the brain. But most of all, an examination of the brain reveals a very specific signature in the form of ìfloride platesî, particular aggregations of pathological prion proteins that cause the neurones to die. As in Alzheimerís disease, they form amyloide plates, but made up of a different protein. This examination is the only one today that allows a positive diagnosis. Unfortunately, it can only be done after the personís death. Symptoms can vary from case to case. The first signs are sometimes confused with psychological problems that could indicate a depressive condition. As it develops, the disease attacks the brain functions and prevents victims from communicating, moving or eating. Death occurs in fourteen months on average, but can sometimes last up to two years. Are there other neighbouring human diseases? The best known is Kuru, which killed about 2,000 people of the ForÈ tribe in Papua New Guinea in the 50s. It was studied by Carleton Gajdusek, who in 1976 received the Nobel Prize for his efforts. He proved that this disease was linked to funeral rites that included cannibalism in which the brain was eaten. No ForÈ born after 1959, when the rite was outlawed, has contracted the disease. Can we be sure that BSE is indeed the cause of the new variant of the Creutzfeldt-Jakob disease? The only absolute certainty would be obtained by willingly infecting humans. But this strong assumption relies on a sheaf of proofs that nobody seems to doubt. For example, mice infected by an injection of tissues of patients having developed the nvCJD and an injection of tissues from cattle with BSE develop exactly the same disease. The same experiment with primates yielded the same results, but lasted much longer. English document on Mad Cow desease Page 12 Is the disease contagious? It is not contagious but is communicable, which is not the same thing. You can live for years in close contact with an infected person without incurring any risk of being contaminated. Beside the cannibal practices of the Kuru epidemic, transmission can occur through contact between the nervous system and infected elements. This can occur, for example, during surgery if an instrument touches an infected zone and is then used on another person. English document on Mad Cow desease Page 13 Does blood transfusion present risks? No studies carried out in cases of the classic Creutzfeldt-Jakob disease concluded that there was a risk in transfusions. However, experiments aimed at detecting the infectious agent in the blood of persons afflicted with the new variant Creutzfeldt-Jakob disease are now underway, making it too early to conclude on the dangers of transfusion. As a precautionary measure, certain countries have decided to ban from the list of blood donors anyone having made an extended stay in countries with a high incidence of BSE, in particular the United Kingdom or France. This risk linked to transfusion is hard to assess, for people who might be incubating the disease are impossible to recognise. On the other hand, excluding too many blood donors through excessive application of the precautionary principle might lead to another health danger, i.e. the lack of blood in hospitals. How many people have been diagnosed with nvCJD? As of May 28, 2001, there are 100 cases in Great Britain. There has been one confirmed nvCJD-related death in Ireland, and 3 in France. How many people will die of nvCJD? Impossible to predict, especially in France where the number of declared cases is too few to serve as a basis for an epidemiological study. British projections are hardly more precise. The uncertainty of the diseaseís incubation time has led to exploring 5 million different scenarios. In the end, the bracket is very wide: from a maximum of 136,000 cases over the next century for incubation times that come close to human life expectancy, down to 6,000 cases over the next fifty years for an incubation time averaging thirty years. What risk has the French consumer been exposed to? This, too, is hard to evaluate precisely, but the main risk probably comes from British offal imported between 1988 and 1994. Up until 1987 these imports were less than 400 tons per year. In 1988 they increased tenfold and continued to increased regularly until they reached 8,000 tons per year in 1993 and 1994. These years correspond to the greatest number of BSE cases in the United Kingdom. The offal imported were those with a high risk of infection, the consumption of which was forbidden in Great Britain. The way in which this offal was consumed in France cannot be known precisely, but it may have been included in meat-based preparations such as mince, certain sauces, raviolisÖ How long does the illness incubate? We donít know. The only way to get an idea will probably be through epidemiological monitoring, but the findings probably will not give precise answers before some twenty years at least. In the meantime, the epidemiological projections of British bio-mathematicians include in their hypotheses an average incubation time extending beyond sixty years. What is the infection threshold of the pathological prion for Man? We donít know. We suppose itís very low. Here again, the only way to measure it would be to infect humans on purpose! As a comparison, it is known that one gram of infected brain is enough to contaminate a cow. We can suppose that a larger quantity would be necessary to contaminate a human, for the disease must leap the species barrier. But so far that is absolutely unproven. English document on Mad Cow desease Page 14 Is everybody as likely to catch the disease? All cases that have appeared up until now concern people who share a common genetic trait. This trait is fairly widespread, since 40% of the population carry it. But not having this trait probably doesnít make people immune to the disease: it may simply prolong the incubation period. This is indeed what was observed in iatrogenic CJD, due to the injection of contaminated extractive growth hormones. Eating habits may also be a risk factor: are people afflicted with the disease big meat-eaters, for example? An epidemiological study along these lines was carried out in Great Britain, but it didnít lead to conclusive results as no link could be made between eating habits and the risk of developing the disease. English document on Mad Cow desease Page 15 7. PUBLIC HEALTH PROTECTIVE MEASURES Is the embargo on British beef still justified? Despite the still significant number of diseased cattle in the United Kingdom, it has not been proven that meat consumed in England is any more ìdangerousî than that consumed in France. But here again scientific certainty is hard to come by. In a report from November, 1999, the European Food and Veterinary Office (FVO) confessed that it couldnít decide between two options: ï considering that the conditions proposed by the United Kingdom for resuming its exportation of de-boned meat2 were satisfactory, and that no proof could be offered that this meat presented a risk for the consumer; ï or putting off the decision about raising the embargo for from 12 to 24 months in order to gather supplementary data. Nearly a year later, in September, 2000, the board concluded that nothing proved that the consumption of whole British veal carcasses, slaughtered between 6 and 9 months, presented any risk. New opinions will probably be given after the publication of studies underway in Great Britain, which aim at clarifying certain points about the present state of the disease among British livestock. 1. The Fvo is made up of 16 members, each representing himself. It is headed by GÈrard Pascal, of the French Inra, and also head of Afssaís scientific board. 2. A few of these conditions: cattle whose meat would be eligible for exportation must be under 30-months old and be born on a farm that has been free of BSE for several years. Their mother must have lived at least six months after their birth without any symptoms of BSE. And, of course, specified risk matter must be scrupulously weeded out. What is SRM (Specified Risk Matter)? For animals that belong to species likely to be affected by BSE, SRM are those parts of their organism in which a prion-infection can be detected at one phase or another of the disease. These parts include the brain, the spinal cord, the eyes, the intestines (and above all their extremities, the ileum) as well as the spleen and the thymus. This list changes constantly as scientific research progresses. Its items must absolutely be eliminated. Though bone marrow is not considered infectious, all cattle bones may soon be prohibited in the fabrication of gelatine. The point of this measure isnít to ban bone marrow, but the vertebrae, which could be infected by surrounding nerve tissues. On the other hand there are no plans to change the production of cosmetic products which use purified cattle fat. These production areas do not seem problematic. Another part of cattle that raised some doubts was the rib on the bone, which is close to the spinal cord. It is a problem that can be detoured by changing the butchering technique at the abattoir. As for the milk and muscle (red meat), they are supposed to not be dangerous for consumption. However, doubts about the innocuousness of red meat are frequently expressed, because muscles contain nerve tissue which might convey the infection. Furthermore, it isnít known if the non-detection of the prion in meat and milk proves it is not there or that the tests are simply not sensitive enough. And in cases where the prion is present in weak doses, we do not know if this quantity could infect humans. English document on Mad Cow desease Page 16 Scientists are inclined to think not. In any case, attempts to contaminate laboratory animals by injections of crushed muscle have never made it possible to observe the diseaseís development. Are we sure we are isolating sick cattle from human food? No, and that is why risky offal has been withdrawn. About 750,000 sick cows are estimated to have been eaten in the United Kingdom. A British researcher estimated that some 100 incubating cows might have entered the food chain in France in 2000. Is systematic culling scientifically justified? More than anything else, it is a measure intended to reassure the consumer, decreed at a time when the number of BSE cases in France was very small. Little scientific data exists for justifying or invalidating this principle. In the United Kingdom, where systematic culling was not practised, it was observed that there were on average four sick cows per farm, and up to fifty in some cases. Two thirds of the English herds had more than one case of BSE. This may seem reasonable insofar as all the cows in the same herd probably ate the same feed. These observations clearly favour total slaughter, but the epizooty reached such proportions in Great Britain that comparison with other countries is difficult. In contrast, studies in Switzerland imply that in a herd where there is a sick cow, the other animals in danger of being ill too are part of the same birth cohort (same age, more or less one year). This argues in favour of selective culling. But these studies deal with insufficient numbers to be able to draw conclusions on a scale of a country like France. The complete findings of the 48,000-test campaign should yield more precise data, better adapted to the French situation. Indeed, a few weeks after the start of this study, it was decided to add to these tests all the animals slaughtered because of the precautionary principle. Pressure from cattle-raisers, who wanted to know if their destroyed herds were afflicted with BSE, lead to this decision. Unfortunately it did not include the first herds slaughtered. Why is it so difficult to harmonise decision-making in Europe? The European Union was not created for health-risk management but to facilitate trade. Anything that might thwart or unbalance this trade is therefore extremely hard to tackle by this institution. For instance, several countries, including Germany, were long opposed to a generalised moratorium on MBM. They were convinced they did not have BSE, and refused to deprive themselves of this cheap source of protein. Moreover, the advent of the single market in early 1993 made it much more difficult to monitor imports and exports. For such measures to be effective, they must therefore be taken on a European-wide scale. But that is not the role of the European Commission, and we return to the beginning of the paragraphÖ Can scientists be of any help in making the right decisions? More or lessÖ Their opinions are only consultative, and the effect of the measures they recommend depends an awful lot on the quality of their implementation, something which scientists simply cannot control. On the other hand, it has now become very difficult for politicians to make decisions in such fields without expert approval. But scientific data are not the only parameters taken into account by decision-makers, who must also consider economic and political realities. English document on Mad Cow desease Page 17 In the end, risk management and communication with the public are really in the hands of the political leaders. Is the public correctly informed about these issues? No, and farmers arenít either. First, the subject is complex. It affects little known diseases for which there are many outstanding question marks. Furthermore, scientific communications are indecipherable for the general public in their original form. Efforts must be made to ìtranslateî and circulate this information, including towards the press. Scientists are not trained to do this, and politicians often prefer to ìfilterî information so as not to create panic. With a boomerang effect that could be gauged in the autumn of 2000 in France when public anxiety was largely fed by the lack of understanding. Were all the precautions taken in time? Probably not. There were delays, and most of all a certain laxness in implementing them. It may also well be that certain decisions were not applicable in practice. On this topic, the Phillips Report might be referred to, as it did an in-depth study of the management of the crisis in the United Kingdom. In France a survey, known by the name MattÈi Report, did a similar job, dealing above all with the suspicions of fraud and illegal imports. Also to be mentioned is the report of the French Senate, published in May 2001, which rekindles the controversy on the tardy ban of bone meal. Finally, there are a number of investigations underway. Is traceability truly a guarantee? In certain cases it can provide security, but it cannot resolve all problems. Firstly, it is not practised in all countries, which is a problem in an open market. Secondly, a certain number of composite and converted products get through completely. Here again the blending and distribution techniques used by the industry are at fault. And of course, it is in these products that the potentially infected tissue may end up, sometimes only by negligence or lack of professionalism. What is at stake in the precautions taken regarding the nvCJD? The cost of these measures might seem disproportionate to the health risk. Considering that the people who will develop the nvCJD are already infected, the implementation of the precautionary principle can be questioned. Is public health the main concern, or is it protecting the politicians, who fear a new scandal comparable to what France witnessed with HIV-contaminated blood? Is the economic future of the cattle industry the real stake? There are obviously no simple answers to these questions. English document on Mad Cow desease Page 18 8. BSE SCREENING TESTS Two screening test campaigns are being jointly applied in cattle. They have common points but also differences. TESTING LAUNCHED IN FRANCE IN 2000 To what purpose? This is above all a research procedure to better understand the extent of BSE in France. It creates an active monitoring network that complements the passive monitoring network in use since '90. This passive network is intended to report all BSE cases detected by a clinical diagnosis of the symptoms. It relies on a network of co-ordinator vets who are named one to a department (96 in Metropolitan France) to centralise and validate all suspicious cases reported by their colleagues after visits to cattle-raisers. What targets? These tests are applied to cattle over 24 months old and considered as risky. This covers several scenarios: ï animals that die in the field or on the farm, whether the cause of death is known or not; ï animals killed in an emergency because of a wound or disease. These tests are therefore not done in a random manner but among cattle that are most likely to catch BSE so as to detect the greatest number possible. What means? These tests are aimed at 48,000 cattle in metropolitan France, i.e. 40,000 in the three major western regions (Brittany, Lower Normandy and the Loire, 12 departments) and 8,000 in all other departments. The number of tests was determined by a statistical calculation relying on the supposed prevalence of the disease (from 0.1 to 3 per 1,000), the number of cattle in France (slightly more than 20 million head) and the precision wished for in the measurement. In addition to these 48,000 tests, there were other tests carried out on animals destroyed as a precaution, i.e. when a test is positive, all the other animals in the same herd are destroyed. It should be noted that this complementary measure was implemented a few weeks after the beginning of the testing campaign and that several hundred cattle were killed and incinerated without their brains being examined. What results? The pilot sampling campaign ended on March 16, 2001. The tests were carried out on 44,000 cattle of the regions of western France, and on 8,600 cattle in other regions as a complementary study. The number of cows tested is therefore slightly higher than initially planned. In a report published on May 29, 2001, the French Food Safety Board (AFSSA) gives its analysis of the test campaign. The tests found 74 cattle in the incubation stage, which represents an average prevalence of some 1.6 per 1,000 amongst the at-risk cattle. This figure cannot be extended to include the entire French cattle population. One must take into account the different categories of cattle amongst which the sick animals were spotted. Indeed, destroyed animals were afflicted by BSE three times English document on Mad Cow desease Page 19 more often (3 per 1,000) than those who died of natural causes (1 per 1,000); nearly 90% of sick cows were born between 1993 and 1995. As expected, this study cannot give formal conclusions on the spread of the disease nation-wide. It can only shed some light on what maximum prevalence can be expected in the worst-case scenario, i.e. amongst at-risk cattle. The study also validates retrospectively some of the implemented measures, such as taking wounded animals out of the food chain. Most of all, this study is a source of data to better understand the disease. It may provide arguments against the systematic culling of herds where a case is found. Tests carried out in Europe in 2001 To what purpose? The tests' main objectives are to increase food safety for consumers, and to regain their confidence by eliminating the largest possible quantity of cattle in the BSE incubation phase. Gradually applied to the entire European Union, these tests should also shed light on the situation in regions or countries that have officially remained free of BSE in an almost miraculous manner. They should therefore help obtain a more realistic picture of the disease on a continental scale. What targets? These tests are for all cattle over 30 months old when slaughtered, even without any symptoms of BSE. Animals this age, who are not tested for one reason or another, are therefore removed from the food chain and destroyed. What means? The European Commission funds a part of the test: 15 euros (about £10) per test, or about 20% of the average cost. Each country has to contribute the complementary means, including the logistics and the choice of accredited laboratories for processing the samples. In France, these tests have been run on more than 700,000 animals during the first five months of 2001. They are on-going, at a rhythm of 30,000 to 42,000 tests per week. What results? As of May 2001, these tests have identified 24 animals in the incubation stages of the illness. This validates the assessments published at the end of the year 2000 by British epidemiologist Chrystl Donelly. Indeed, she surmised that about 100 infected, but symptom-free, animals may have been included in the French food chain during that year. Looking at the cases detected by the tests, it appears that the regions of western France are the hardest hit, though the illness has also been spotted in some departments of eastern France. The extent of the campaign has helped boost consumer confidence in bovine meat. However, it mustn't let people believe that the French food chain is now perfectly free of infected animals. English document on Mad Cow desease Page 20 Indeed, though rapid tests can detect the illness many months before the first symptoms appear, they cannot pinpoint sick animals in the early stages of incubation. As AFSSA has clearly stated, the systematic testing should not dampen the scrupulous control over the elimination of SRM. This remains the centrepiece in the system of public health protection. Finally, it should be noted that 170,000 cattle over 30-months old were slaughtered without being tested, between January 1, 2001, and May 20, 2001. Of course, they were not included in the food chain, but incinerated. This measure was taken for economic purposes, to support the cattle industry and prevent market decline. Although these test-less slaughters did not incur any risks for public health, it is nevertheless a missed occasion to collect scientific data. Other questions on the screening test Which rapid tests have been approved in Europe? The Biorad test has been perfected by the CEA (French Centre for Atomic Energy) and developed by the American company, Biorad France. Prionics is a Swiss test from the Prionics AG company, produced and sold in France by the AES laboratory in Brittany. This is the one selected for the campaign of 48,000 tests begun in mid-2000 in France. The Irish test, Enfer (Enfer Technology, Ltd.) is the third test approved by the European Commission. Five other tests from the following agencies are being studied: Id-Lelystad, Holland; Imperial College of Science Technology and Medicine, United Kingdom; The Institute of Neurodegenerative Diseases / University of California, San Francisco(IND/UCSF), United States; PerkinElmer Life Sciences, United Kingdom; Prionics AG (Elisa), Switzerland. There is also a complement to the CEA France test that may make it possible to distinguish BSE from scrapie. How were they chosen? The European Commission received ten applications from test producers. The four most promising on paper were then assessed in the field on a series of 1,400 samples from both healthy and sick animals. 1,064 samples were taken from 1,000 healthy animals, and 336 were done from animals who had been confirmed as BSE cases. How reliable are these rapid tests? Three of the four tests correctly identified all the samples that they were given ìblindî. The fourth test found 70% of the sick animals and 90% of the healthy ones. It was not approved. Generally speaking, the approved tests are more sensitive than those used to detect diseases such as undulant fever and tuberculosis, even when used in advanced stages of these diseases. ìDilutionî trials were also run. These consist of trying to spot the infectious particles mixed in at ever weaker concentrations with healthy tissue. In this trial the Biorad-CEA test proved to be the most effective. It was able to detect prions in an infected brain that was crushed up and diluted to 1%. The Prionics test showed it was limited in this area English document on Mad Cow desease Page 21 to concentrations about ten times higher, and the Enfer test performances were somewhere between the two. What is the principle of the BSE screening tests? The general principle is the use of a specific antibody capable of binding to the prion protein. Whether the protein is the cause of the disease or just a tracer is of little importance at this stage. This method can undergo changes to make it faster to implement and to ease its mass application, especially in rapid test cases, but is based on the principles commonly used in biochemistry to recognise and distinguish proteins. The problem with prion proteins is in distinguishing the pathological form incriminated in BSE from the healthy form, which all mammals carry. Indeed, the antibodies used are not able to distinguish between these two forms. The solution is to first eliminate the healthy prion proteins from the sample by attacking them with an enzyme. This reaction is the one that occurs naturally in the organism. It does not affect the pathological proteins, which resist elimination. If there are infectious prions present, they will thus be the only ones to resist destruction by the enzyme and to be recognised by the antibodies. The fast test is applied to samples taken from the brain stem. Results are obtained within a few hours. The specifics of each test lay in the use of different specific antibodies, each then being observed in its own way. Are these tests the only way to detect BSE? No, the above-mentioned tests are ìrapid testsî. They are not considered to be reference methods and must then be confirmed by immunocyto-chemistry (the examination of histological crosscuts of the brain) or by ìWestern-blotî. In a ìWestern-blotî, a protein associated to its specific antibody migrates by electrophoresis in a gel where it leaves a marking specific to its chemical composition (mainly of its molecular mass), as a kind of signature. This technique is very routinely used in biochemistry. For example, it is used for finding other specific proteins that appear in Alzheimer's disease. One of the goals of the 48,000-test campaign done in France is to compare the results of the Prionics rapid test with the more traditional ìWestern-blotî method. It should be noted that the rapid test does not make it possible to detect the infection earlier than the other methods. It is simply useable on a mass scale, which is a clear advantage. What more can be asked of these tests? To detect the infection earlier. To detect the incubating animals as early as possible, during the long five-year period before any symptoms appear. Measurements in the intestines and above all in its extremity, the ileum, would be interesting. This is the first organ to be infected, but on a level too low to be detected by present means. This method has already led to a few results, but only in cases of experimental infection obtained with large doses of infecting matter. Ideally, it would be possible to test living animals by non-invasive sampling, e.g. with blood or urine. No technique to do this was yet been found. This might first be feasible in sheep prior to death from scrapie, as the infection spreads more widely than in cattle and is seen outside the central nervous system. English document on Mad Cow desease Page 22 It is hoped that eventually a test for the massive screening of all living cattle will be available and that the disease will thus be quickly eradicated. Another research avenue is perfecting a test to detect the infection among humans. English document on Mad Cow desease Page 23 9. SHEEP AND OTHER ANIMAL SPECIES What animal species are affected by the TSSEs (transmissible subacute spongiform encephalopathies)? BSE may be the most ìfamousî of the TSSEs, but it is not alone. Sheep scrapie appeared in Europe in the mid-18th century, and has since been widely exported. It was suspected of being at the source of the BSE epizooty through sheep carcasses being recycled into meat and bone meal. But this has not been proven, and the original infection may well have come from a sporadic case of BSE, unknown to veterinary medicine. Under scrutiny for more than two centuries, scrapie has clearly never crossed the species barrier to contaminate mankind. On the other hand BSE has contaminated cats, probably through feed containing offal. Some eighty cats were thus contaminated in England in the early ë90s with Feline Spongiform Encephalopathy. Minks in the United States have suffered from a similar disease known as TME (Transmissible Mink Encephalopathy). This contamination probably originated from the sheep and cattle carcasses used to feed minks on mink farms. It spread rapidly because minks are carnivorous animals that eat the other minks that die around them. Other ruminants in North America have been affected too: moose, stag and wapiti deer. Wapiti deer are sometimes raised on farms, but stags and moose are wild animals, making epidemiological studies difficult. It is nonetheless estimated that the proportion of afflicted animals in Wyoming varies between 6 and 15%. The origin of this disease may also be found in the bone meal that is sometimes made available to these animals in the winter months. This disease, known as Chronic Wasting Disease or CWD, raises an important question: is it or is not transmissible to humans? Three hunters under thirty died of the Creutzfeldt-Jakob disease in Utah in 1998. The possible link between these cases and CWD is being evaluated. Are sheep in danger of being contaminated by BSE? It has been proven in laboratory conditions that the BSE bovine agent is capable of infecting sheep orally. They develop a disease that is very hard to distinguish from scrapie but could have much more harmful consequences for humans. To date, this contamination by the BSE agent has never been observed in a natural setting in herds. But the similarities between the two diseases call for very intense monitoring to ensure that sheep do not develop this form of BSE. Indeed, although it has not been a general rule, that sheep may have consumed animal meal cannot be excluded. Moreover, because monitoring facilities have been bolstered in France, the number of reported cases of scrapie in 2000 has increased, which calls for even more vigilance. What threat would this sheep disease represent? In contrast to scrapie, it could easily be passed onto humans for it is caused by the same infectious agent as BSE, which has shown what harm it can do among humans. Whatís more, although the cattle disease remains limited to the nervous system and does not seem to infect tissue such as the muscles, it would not necessarily be the same for sheep BSE. A larger part of the organism would be affected, in particular the ganglions. Recourse to the total destruction of the animals would be necessary and not just a withdrawal of Specified Risk Matter. English document on Mad Cow desease Page 24 The possibility that this variant of BSE might appear is sufficiently serious for AFSSA to have published a report about it in July, 2000, and a warning in February, 2001. It has also worried the British Food Safety Board, which has called for a very careful monitoring of all cases of scrapie. Is there any relationship between foot and mouth disease and BSE? On the health and biological levels, they are two different diseases without any points in common. Foot and mouth disease cannot be passed on to humans. However, it can be argued that the extent of these diseases point to insufficient surveillance and preventive measures. Indeed, the fact that both epidemics broke out in the United Kingdom after the health services had all but been taken apart, may not be haphazard. English document on Mad Cow desease Page 25 10. WHAT WE HAVE (TEMPORARILY) LEARNED FROM THE CRISIS Can fingers be pointed? It seems extremely hard.Some cattle raisers probably ran the risk of buying cheap bone meal soon after it was prohibited in the United Kingdom. Others were tardy perhaps in declaring suspicious cases of sick cattle. Still others may have unknowingly fed their animals with infected meal after theyíd been mixed in with feed supplements. But generally they have undergone a production-oriented system that shows them clearly how to improve their income and supply products that meet market needs. There were probably also illegal imports and a lack of rigour in the manufacturing of certain feed. But with the animals showing the first signs of the disease only several years after being infected, it is generally impossible to establish a direct cause-and-effect link. As with the ìpoolingî techniques, mistakes and corruption add up and spread all over the country, even the continent. True responsibility for the disease and its consequences for mankind must most certainly be sought in a global social model rather than with identifiable real persons or legal entities. By intensifying cattle raising and above all by making cows produce a lot more milk than they can do by just eating forage, we have made food correctors and protein supplements a necessity. Every step in this crisis, which, in hindsight, might appear to be a reprehensible mistake, was seen at the time as an intelligent way to increase productivity and profitability. And then there is the question of political leadership. This has been the object of several reports, some more controversial than others. Should the production systems be changed? This crisis can be seen as that of a food production system. It concerns the entire cattle-raising and cattle products industry. This is an industry that made enormous efforts to lower its production costs in a few dozen years, with a highly laudable view to supplying meat and milk products to the entire population at affordable prices. In many countries, attaining those goals has compelled the cattle industry to enter an industrialised period and to become intensive. The agricultural revolution has succeeded well beyond its initial goals, creating a situation nearing over-production. But habits die hard, and the rationale of optimal productivity has continued to develop without retreating. The ìmad cowî crisis has now cast a new light on the situation, and calls for a return to reasoned farming are increasing. Numerous players in the cattle industry say they are ready to go back to square one in their practices and to think about other production methods. We will have to wait a few more years before seeing if, beyond statements aimed at reassuring the consumer, lessons have truly been learned from this crisis. What will cattle eat tomorrow? The total ban of meat and bone meal raises questions, including what is going to replace it in cattle feed. Although the most obvious solution consists of using plant protein, it runs aground on certain shoals. Indeed, the agreements signed within the framework of the World Trade Organisation (WTO) supervises very closely the aid each country may allocate to its farmers for producing oil-producing grains. France English document on Mad Cow desease Page 26 may be compelled to import large quantities of plant protein, a goodly part of which may be developed from GM (genetically modified) grains. The long-term consequences of using GM foods are to date totally unknown, and the implementation of the precautionary principle is caught in a crossfire. There may however be a solution for getting round these difficulties. It would mean giving up supplementing cattle feed with proteins and letting cows produce their ìnaturalî quantity of milk. Obviously such a solution would reduce productivity. Will Europe learn to manage health risks? The draft proposal for creating a European Food Safety Authority is without a doubt a very interesting initiative. It will have to be given time for implementation and then find its operational cruising speed before we can judge its effectiveness. There are a lot of potential questions concerning its independence, its possible powers (not just consultative) and its ability to go counter to the commercial and industrial interests of European member countries ñ all the more complex in that they are different from one country to the next. Yet this project is the only hope at present for Europe, on agriculture and health issues, to expand its expertise in subjects other than just arbitrating trade conflicts. English document on Mad Cow desease Page 27