Abstract

Since the recognition of BSE in 1986, over 180,000 cattle in the UK have developed the disease and 1–3 million are likely to have been infected with the BSE agent, most of which were slaughtered for human consumption before developing signs of the disease. The origin of the first case of BSE is unknown, but the epidemic was caused by the recycling of processed waste parts of cattle, some of which were infected with the BSE agent, to other cattle in feed. Control measures have resulted in the consistent decline of the epidemic in the UK since 1992. Cattle and feed exported from the UK have seeded smaller epidemics in other European countries, where control measures were applied later. If the control measures now in place to protect public and animal health are well enforced, the epidemic in cattle should be largely under control and any remaining risk to humans through the consumption of beef should be very small.

BSE is a zoonosis1. The mode of transmission to humans in not known with certainty, but BSE has been shown to be readily transmissible experimentally by the oral route in both cattle and sheep and this seems the most likely route in humans, given that it is known that very large numbers of cattle incubating BSE entered the human food chain. The risks of human infection have changed over the years since the discovery of BSE in 1986. At that time there were no protective measures in force; even when measures were introduced from 1988 onwards, they were not always enforced with the diligence necessary to completely protect public and animal health2. Furthermore, during the course of the epidemic, research and epidemiological analysis have revealed additional information of relevance to the protection of public and animal health as a result of which further legislation has been introduced. For example, although around 180,000 cases of BSE have been confirmed in Great Britain, it has been estimated, based upon mathematical modelling of the BSE epidemic, that of the order of 1–3 million cattle may have been infected with the BSE agent3,4. Most of these infected animals were slaughtered for human consumption before there were any clinical signs of BSE.

Though initially reported in the UK, BSE has had a global impact on trade in cattle and cattle products as well as on public and animal health. The cost of the BSE epidemic in the UK alone has been estimated to be in excess of £4 billion5.

Origin of BSE and the BSE epidemic

The origin of the first case of BSE is unknown, though several theories for this have been put forward. The origin of the epidemic of BSE following the first case is much clearer and, although some uncertainties remain, the recycling of bovine tissues back to cattle in feed is the most plausible explanation for the fuelling of the epidemic and this provided the key to controlling the spread of the disease through restrictions placed on such recycling.

Recognition of the epidemic and initial investigations

The first confirmed cases of BSE were in Great Britain in 1986, following referral of the brain of two cows with unusual progressive neurological signs from two veterinary investigation centres in southern England to the Pathology Department of the Central Veterinary Laboratory (now the Veterinary laboratories Agency – VLA). The disease was recognised as a spongiform encephalopathy because of the neuropathological similarity to that seen in the sheep disease scrapie (see Hunter in this volume). The pathology had not been described in cattle previously and BSE was classified as a new disease. It is likely that cases of BSE preceded the identification of these first confirmed cases but were not diagnosed. There was retrospective evidence of the occurrence of clinical disease in April 19856 but it is likely that the first cases may have occurred in the early 1980s or even in the 1970s2,7.

After the confirmation of the first cases, increasing numbers of cases were diagnosed in the following year and there was recognition that this might be an epidemic of a new disease in cattle. Epidemiological investigations were initiated to try to find clues to the cause of the disease. These studies revealed that the use of meat-and-bone-meal (MBM) as a high protein supplement feed was a linking feature on the farms from which cases had been reported6,8, and this might be the vehicle of infection. Further evidence in support of this hypothesis was the higher incidence of BSE in dairy cattle than in beef cattle. This excess has been maintained throughout the epidemic and the likely reason is because the latter are suckled, often for long periods and are not usually fed concentrate rations during their initial period of growth and sometimes not at all or at a low rate. By contrast, calves from dairy cows are removed from their dam soon after birth and the calves are initially reared on milk substitutes and are soon weaned on to a diet of hay and concentrates that often contained MBM.

The cause of the epidemic

MBM is produced from rendering the waste parts of mixed species including sheep and cattle that are not suitable, or not used, for human consumption. Rendering is the process whereby the waste tissues were processed to separate protein from fat.

MBM was incorporated into concentrate rations as a high-protein supplement. It was fed to cattle and, to a lesser extent, to selected sheep but its main use was in pig and poultry rations at higher inclusion rates than for ruminant animals. In the 1970s and 1980s, the source material for these end-products was from all species of farm animal including fallen stock (animals dead on farm), abattoir and butcher's waste, and condemned materials. The starting materials were cooked by various methods to evaporate water to steam and the tallow (fat) was separated by centrifugation or pressing, leaving a solid material called greaves from which MBM was derived by grinding.

It was hypothesised that once the causative agent of BSE had been introduced into the rendering process it would be recycled to infect other cattle through MBM. The waste tissues of these infected animals would then go into rendering processes when they were slaughtered and consequently the epidemic would be further propagated through MBM. Research demonstrated that none of the rendering processes in use in the European Union (EU) at the time was probably completely effective at inactivating either the BSE agent or a range of scrapie agents, though some were better than others in lowering infectivity titres of the agents9,10.

Because it appeared that the incubation period of BSE was, on average, 5 years, the infection must have been introduced in the late 1970s or early 1980s and many cattle had been infected before the epidemic was recognised.

A problem with this hypothesis was that MBM had been used in animal feed for decades so the cause of BSE was either the new occurrence of the BSE agent in starting materials used in rendering, or an increase in the exposure of susceptible species to the agent6. Wilesmith and colleagues identified changes in the processes used to extract tallow by the rendering industry in the late 1970s and early 1980s that might have been responsible for the presumed increase in titre of TSE agents in MBM and consequently the increase in exposure of cattle6. It was further postulated that BSE occurred in the UK first, rather than in any of a number of other countries which had similar rendering systems, because the ratio of sheep to cattle tissues going into rendering was higher in the UK. This would potentially increase exposure to a cattle-adapted form of scrapie, which might be the cause of BSE. In a more recent enquiry into the origins of BSE7, it was noted that the UK was the first country to start feeding MBM to young calves in the 1970s (though other sources11 suggest this was at least 20 years earlier). Because it appears that young cattle may be particularly susceptible to infection with the BSE agent3,7, this may be why the epidemic started in the UK.

Origin of BSE

It was clear how recycling through MBM may have fuelled the BSE epidemic, but there must have been a first case of BSE to seed the epidemic. What was the origin of this? There has been an intensive search for the answer to this and to other key questions, such as: why did the epidemic start in the UK and why did it start when it did? Despite several theories, these questions remain essentially unresolved and may remain so.

Because the neuropathological appearance of BSE was similar, though not identical, to that of scrapie in sheep, a leading contending hypothesis has been that the origin of BSE was from a scrapie-like agent from sheep or from cattle infected with a cattle-adapted scrapie-like agent6,8. Scrapie is a TSE of sheep that has been known to be endemic in the UK for over 250 years and must have been maintained within flocks by sheep-to-sheep transmission. Scrapie is not classified as a zoonosis as there is no evidence that it is pathogenic to humans. The disease also occurs, though less frequently, in goats and moufflon. Scrapie has a wide-spread distribution with a variable and generally imprecisely known prevalence in Europe, North America and Japan. Although scrapie must transmit naturally from sheep to sheep to maintain the agent in the sheep flock, the mode of transmission between sheep remains uncertain. There is no evidence to support direct transmission of scrapie from sheep to cattle and early studies on BSE showed that the disease was equally common on mixed sheep and cattle farms as on cattle-only farms. However, sheep tissues infected with scrapie agents could have been the origin of infection for cattle via feed because these materials entered the rendering system and after processing, entered the ruminant feed chain, thus offering a plausible origin for BSE.

A major problem with this hypothesis, however, is that the strain of TSE agent causing BSE is biologically and molecularly distinct from any of the many strains of TSE agent causing scrapie that have so far been identified (see Bruce, this volume), even though experimental transmission of BSE to sheep and goats has been successful by the oral route12.

An alternative hypothesis for the origin of BSE is that the disease occurs sporadically at very low frequency in cattle and, unluckily and by chance in the UK, tissues from such a case was incorporated into MBM to seed the epidemic. There is no direct evidence for the occurrence of sporadic cases of BSE in cattle, but if the disease was very uncommon odd cases may well not have been diagnosed in the absence of the propagation of an epidemic through recycling in feed.

The theories mentioned above are generally considered the most plausible, but a variety of other explanations have been advanced with varying degrees of credibility7,13.

Animal health control measures and their impact

The ruminant feed ban

Once the likely cause of the BSE epidemic had been identified, controls were put in place in 1988 to ban the feeding of ruminant protein to ruminants. Ruminant-derived MBM was still permitted to be fed to pigs and poultry as these animals were not thought to be susceptible to infection with the BSE agent. This feed ban had a major effect on the epidemic. The effect was not immediately apparent because of the long incubation period, exposure generally occurring in young dairy calves but the disease only being manifested, on average, 5 years later. However by 1992, the measures had impacted on BSE cases and subsequent to that year the numbers of cases have fallen by about 40% a year on average (Fig. 1).

Fig. 1

Number of cases of BSE in Great Britain by year of onset.

Fig. 1

Number of cases of BSE in Great Britain by year of onset.

Cases born after the ban

The feed ban had a major impact on the epidemic, but it was not as effective as had been hoped and cases of disease continued to occur in animals born after the feed control measures had been introduced (Fig. 2) and now over 44,000 cases have been reported in animals born after the date of the ban. Epidemiological studies on these ‘born after the ban’ (BAB) cases revealed that the greatest incidence was in eastern England, corresponding to the area with the greatest prevalence of pig farms. Further investigation led to the hypothesis that BAB cases of BSE might be attributable to accidental cross-contamination of ruminant diets with MBM intended for pigs and poultry14. The discovery that less than 1 g of infected cow brain could experimentally transmit BSE to further cows by the oral route lent weight to this hypothesis, as only a relatively small amount of such contamination would be required to induce disease.

Fig. 2

Number of cases of BSE in Great Britain by year of birth.

Fig. 2

Number of cases of BSE in Great Britain by year of birth.

The re-inforced feed ban of 1996 and subsequent cases

Various measures were taken to strengthen the feed ban in the early 1990s and, following the report of the first cases of variant Creutzfeldt-Jakob disease (vCJD) in 1996, a total ban was placed on feeding mammalian protein to any farmed animals, with an associated recall of existing contaminated feed stocks from farms. It was hoped that this would totally close off the feed route that had fuelled the epidemic. The feed ban that was introduced in the UK in 1996 was essentially the same as the feed ban that was introduced across the EU in 2001, 5 years later.

It was expected that there would be a small number of cases of BSE born after mid-1996, even if the mammalian feed ban had been totally effective. This was because the feed ban would not have impacted on cases of BSE due to maternal transmission. Although it is not certain that this route of transmission exists, a cohort study suggested that there might be a 10% risk of such transmission to calves born within 6 months of clinical onset of BSE in the dam15,16. To date, there have been 57 cases of BSE with birth date after August 1996, but it seems unlikely that maternal transmission is the explanation for these cases. Epidemiological investigations are on-going to try to find clues to the origin of these cases; to date, no convincing explanation has been found except for one imported case. Given the experience of the partial success of the 1988 feed ban, the favoured hypothesis must be that the cases born after mid-1996 are due to some residual leakage of contaminated feed, through a route yet to be identified. It has been proposed that infection could be attributed to cross-contamination by infected feed or feed ingredients containing infected MBM imported from EU Member States with BSE in their native-born cattle before the imposition of the EU-wide mammalian feed ban on 1 January 200117. However, the possibility of non-feed routes of transmission cannot be excluded. These may have been of minor importance in the past, but may be now more evident as the feed route has been finally closed off. Importantly, the number of cases born after mid-1996 remains low at a time when animals in the 1996/1997 birth cohort are at a peak-risk age for clinical BSE. Thus, in summary, although the epidemic in the UK is not over yet, the number of cases has declined consistently year-on-year since 1992 and the vast majority of cases that are now being reported are in animals born before 1996.

BSE outside of the UK

Initially, BSE was regarded as a disease problem confined to the UK, but there were soon indications that other countries to which cattle, cattle products and MBM had been exported were also at risk. BSE has now been identified in cattle in most European countries and more recently in some countries outside of Europe. Following the announcement in March 1996 of the occurrence of 10 cases of vCJD in humans in the UK, there has been an up-surge both in the numbers of countries reporting BSE for the first time and in the numbers of cases in all countries except the UK. The sequence of reporting the first case of BSE in different countries is shown in Table 1. It is highly plausible that the epidemics of BSE in European states other than the UK were seeded either by cattle exported from the UK that were incubating BSE, or through the export of MBM contaminated with the BSE agent. However, processes similar to the rendering processes that were prevalent in the UK were also practised in some other European states. Once the infection had been introduced into cattle, it seems highly likely that it was recycled to other cattle through MBM in the same way as happened in the UK.

Table 1

Sequence of first report of BSE in native-born cattle

1986 UK 
1989 Ireland 
1990 Portugal, Switzerland 
1991 France 
1997 Belgium, Luxembourg, The Netherlands 
1998 Liechtenstein 
2000 Denmark, Germany, Spain 
2001 Austria, Czech Republic, Finland, Greece, Italy, Japan, Slovakia, Slovenia 
2002 Israel, Poland 
2003 Canada 
1986 UK 
1989 Ireland 
1990 Portugal, Switzerland 
1991 France 
1997 Belgium, Luxembourg, The Netherlands 
1998 Liechtenstein 
2000 Denmark, Germany, Spain 
2001 Austria, Czech Republic, Finland, Greece, Italy, Japan, Slovakia, Slovenia 
2002 Israel, Poland 
2003 Canada 

Around 180,000 confirmed cases of BSE have been reported in Great Britain with around a further 2000 in Northern Ireland. Of other affected countries, only the Republic of Ireland with around 1200 cases has more than a thousand. France has reported more than 800 cases and Portugal more than 700 whereas Canada, Finland, Greece and Israel have reported only one each (as at July 2003). France has the largest cattle population in the EU, so the BSE incidence there is little different from that in other countries in continental Europe with fewer cases.

Because, in general, control measures on feed were put in place later outside the UK, the epidemic curves have taken a different shape in other countries; in particular, whereas the peak of the UK epidemic was in 1992, it has been at a much later date in other Member States. Figure 3 shows the epidemic curves in selected European countries. The figure illustrates the impact of the different times that restrictions put on feed in the different countries became fully effective. The ban on the feeding of mammalian MBM to all farmed animals that was put in place in the UK in 1996 was only implemented throughout the EU from January 2001. These measures, if correctly enforced, should have eliminated transmission by feed, or at least reduced it to very low levels. However, it will still be some years before the full impact will be manifest in the decline in detected cases of BSE, because of the long incubation period of the disease. It is encouraging to note that most European countries are now showing a reduced annual incidence of BSE.

Fig. 3

Number of cases of BSE in selected European countries by year of onset.

Fig. 3

Number of cases of BSE in selected European countries by year of onset.

Control measures to protect human health

Specified risk material (SRM) controls and tissue distribution of the agent

The distribution of the BSE agent in different bovine tissues in infected animals is very uneven. The distribution of infectivity was assessed initially by injecting different tissues from clinical field cases of BSE into the brains of mice and the mice were kept to observe the subsequent appearance of disease due to BSE. Subsequently, these experiments have been extended for a range of tissues at specified times of incubation by injecting the tissues from cattle with experimental BSE into the brains of both mice and calves. The latter study avoids the lack of test sensitivity due to the crossing of a species barrier (from cattle to mice). The results of these studies have shown that, in natural cases of BSE, detectable infectivity is restricted to the brain, spinal cord and retina18 and third eyelid (GAH Wells, personal communication). However, in experimental, orally-induced BSE, infection has been found in the distal ileum from an early stage after infection and for most of the incubation period, in the tonsil at an early stage of incubation19 and in the central nervous tissues including the brain, associated ganglia, the spinal cord and dorsal root ganglia from about 3–6 months prior to clinical onset and in the clinical stage only, in sternal bone-marrow20. Mammary gland, milk, skeletal muscle, liver, kidney, all male and female reproductive tissues, fetal blood and placenta have shown no detectable infectivity.

Clinically suspect or confirmed cases of BSE were banned from the human food chain in the UK in 1988 and in the EU in 1990. The uneven distribution of the BSE agent in different bovine tissues has been the basis for the most important EU-wide measure to protect consumers from infected tissues from pre-clinically affected cattle – the specified risk materials (SRM) ban. The first control measure with respect to tissues from cattle without clinical evidence of BSE was introduced in the UK in 1989 when a specified bovine offal (SBO) ban was instituted. This prohibited bovine brain, spinal cord, tonsil, thymus, spleen and intestines from entering the human food chain. The SBO ban preceded the mouse and cattle assay experiments outlined above and the choice of prohibited tissues was based upon the known distribution of the scrapie agent in sheep, which had been studied for much longer. In 1990, the SBO ban was extended to protect all animal species and such bovine tissues were prohibited for use in MBM. Further adjustments to the ban have been made in the UK and a similar ban has been introduced throughout the EU since 2000. Tissues included in the SRM ban have been estimated to include of the order of 99% of the infectivity in a BSE-infected bovine. From the introduction of the SBO ban in 1988, this ban on specific bovine tissues is likely to have been the most important measure in protecting humans from the risk of BSE infection through food.

The over 30-month rule

Following the announcement of vCJD in March 1996, the committee that advised the UK Government on scientific aspects of transmissible spongiform encephalopathies (TSEs), the Spongiform Encephalopathy Advisory Committee (SEAC) recommended that, to reduce the risk of human infection with the BSE agent, meat from cattle over 30-months' old should be de-boned and the obvious nervous and lymphatic tissue removed and treated as SRM. In the event, the UK Government decided, for practical reasons, that no British cattle over 30-months' old should be consumed. Instead they should be slaughtered conventionally but all parts should be incinerated, in other words treated as SRM. This over 30-month (OTM) scheme is still in existence but the Food Standards Agency, which is responsible for food safety issues in the UK, has recently recommended to the Government that the rule be abolished for cattle born after 1 August 1996. This recommendation was made following a risk assessment21 which indicated that the risk for the public in consuming meat from such cattle has now fallen to a very low level. By 2005, it is proposed that the rule will be abandoned completely. However, the scheme will be replaced by compulsory ‘rapid’ testing of the brain from all cattle slaughtered for human consumption over 30 months of age as is already done elsewhere in the EU.

Active testing for BSE

Until relatively recently, the monitoring of the BSE epidemic in the UK and other countries was through a ‘passive’ surveillance system whereby clinical cases of suspected BSE were reported and then investigated pathologically to confirm the diagnosis of BSE. In the UK, farmers, veterinarians, State Veterinary Officers and others directly associated with live cattle were informed about BSE, and Ministry staff were trained to recognise the clinical signs. BSE was made a notifiable disease and animals suspected to be affected with BSE had to be officially reported and investigated. Similar processes were followed in other Member States of the EU and elsewhere, once the international nature of BSE was acknowledged.

During 1999, the Swiss veterinary authorities reported targeted testing of cattle at risk from BSE, namely fallen stock, emergency slaughter animals and in adult cattle in abattoirs. A rapid test for the misfolded form of host protein (PrP) was used on brain material. The initial results identified that several cattle in the above categories were infected by BSE but no clinical evidence of disease had been reported. During 1999, the European Commission (EC) evaluated four so-called ‘rapid’ tests for BSE and approved three for use for active surveillance22; more have been evaluated since. The tests were formally targeted to all fallen stock and emergency slaughter cattle over 24 months of age and all slaughter cattle over 30 months of age in all Member States. This necessitated a change to abattoir procedures since no part of any animal could leave the abattoir for the food chain unless accompanied by an official health stamp and a negative test result. However, the UK was excused testing all of the animals in the OTM scheme as these were not permitted into the food chain in any circumstances.

A major value of such testing was to increase knowledge about the occurrence and risk from BSE in the EU. There had long been concern that reliance on passive reporting for clinical cases of BSE had led to under ascertainment of the magnitude of the disease problem, due to failings in reporting systems. In addition to improving surveillance for BSE by the use of an objective test applied to all animals passing through abattoirs, the testing also provided consumers with a degree of confidence that the meat they ate came from animals with no positive evidence of BSE infection. However, since cattle could be infected as calves and infection cannot usually be detected in the brain until some 3–6 months before clinical onset, it was still possible that some cattle could contain infection but provide a negative test. Nonetheless, such testing combined with the stricter controls on feed, and SRM removal will have contributed significantly to lowering the risk to consumers.

Current issues and future prospects

As a result of the imposition of control measures, the epidemic of BSE in the UK has declined by 25–45% a year since 1992. The cause of the cases born after mid-1996 is unknown, but their number is small and given the control measures in place, it is unlikely they will have significant impact on animal or public health21. There are smaller epidemics in other counties which are earlier in their course, but the mammalian protein feed ban for all farm species, in place across the EU since January 2001, should greatly reduce the incidence levels in the birth cohorts born after that date. The SRM controls which are designed to prevent high-risk bovine tissues entering the human food chain also greatly reduce the possible risks to human health and the testing for BSE of all animals over the age of 30 months slaughtered for human consumption provides further protection in addition to the SRM controls. The epidemic of BSE was caused by the recycling of bovine tissue in cattle feed and maintaining controls on this should stop the re-emergence of BSE as a significant animal health problem. Priorities for the future must include continuing to monitor the level of BSE infected cattle and to enforce controls on high-risk tissues from entering the food chain.

The full impact of the BSE epidemic on human health may not be assessable for many years. It is likely that millions of individuals were exposed to contaminated beef products, but to date less than 150 cases of vCJD have been diagnosed globally. The possibility cannot be excluded at this stage that the incubation period is very long, possibly several decades on average, and that the peak of the human epidemic is still to occur, though there has been a fall in a number of deaths from vCJD in the UK in recent years23.

Cases of BSE will continue to arise for at least some years to come because of the long incubation period of the disease but be restricted to progressively older animals if the feed ban is effectively enforced and there are no other means of transmission. However, the numbers of infected animals entering the food chain now is likely to be at a low level and the bovine tissue controls in place should ensure that any risks to human health are very low and diminishing year-on-year. It is impossible to predict when the last case of BSE will occur, but the risk to public health from cases of BSE arising now in unlikely to be large, provided existing controls are rigorously enforced.

Correspondence to: Peter G Smith, Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK

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