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The BSE Inquiry
Issued 14/10/1999

Discussion Document for SESSION on Epidemiology of BSE

14 October 1999

INTRODUCTION AND PURPOSE OF SESSION

The object of the session is to assist the Committee with respect to that part of their terms of reference that requires them to establish and review the history of the emergence and identification of BSE. The hearing will consider the different hypotheses as to the origin of the BSE epidemic, taking into account all the data now available. For this purpose we shall be considering the material facts with the benefit of hindsight. This session is not intended to address that part of the Committee's terms of reference that requires them to reach conclusions on the adequacy of the response to the emergence and identification of BSE and new variant CJD taking into account the state of knowledge at the time.
In the early days of the epidemic, the most widely supported theory was that BSE in cattle was caused by the agents that caused scrapie in sheep, a disease which had been in existence for at least two hundred years, and which had not, hitherto, resulted in disease in either cattle or man. It was theorised that the scrapie agent had now passed into cattle. We shall describe this theory as "the Scrapie Origin Theory."
The Scrapie Origin Theory does not address the question of what risk is posed to humans by BSE. It has been pointed out that transmission of scrapie from sheep to cattle might have led to alterations in the population of scrapie strains, such that the resultant cattle strain or strains could be more, or less, pathogenic for humans than sheep strains. Nevertheless the Scrapie Origin Theory led many to conclude that BSE in cattle was very likely to behave like scrapie in sheep, so that it would not transmit to humans. It influenced decisions as to the precautions that should be taken in relation to BSE and views as to the importance of those precautions.
The importance of the theory is exemplified by a letter written by Sir Donald Acheson to Professor John Pattison in January 1996.⁽¹⁾ He wrote, 'the basis for the reassurance that we gave the public ('beef is safe') rested on the analogy to scrapie' and said that the assumption that the epidemic was due to the presence of the scrapie agent in MBM was 'now less secure than it was' at the time of the Southwood Report.
The theory that BSE was caused by conventional scrapie agent or agents in cattle rested on a number of observations and assumptions. At the hearing the Committee would like to explore each of these assumptions, in particular the assumption that this was an epidemic with an extended common source. In the light of this evaluation, they would like to discuss alternative hypotheses as to the origin of BSE.
There are some further issues the Committee would like to explore if time is available, relating to maternal transmission and BABs, and to the within-herd incidence of BSE in affected herds.
Those who will be participating in the epidemiology session on 14^th October 1999 have been asked to set out in writing their thoughts on the issues raised by this paper. The Committee appreciates that not all participants will be in a position to make an informed contribution on all of the matters raised.

ASSUMPTIONS UNDERLYING THE SCRAPIE ORIGIN THEORY
When first put forward, the Scrapie Origin Theory referred to a number of observations, assumptions and hypotheses. Among these were:

a) Pathological findings (e.g. light microscopic similarities and presence of scrapie associated fibrils) in cattle provided evidence that the aetiology of BSE was related to that of scrapie. The disease had close similarities to natural scrapie of sheep and related transmissible spongiform encephalopathies.

b) The main common factor in affected cattle was the consumption of cattle feed containing MBM. MBM was prepared from animal protein rendered from carcase waste, mainly from sheep, cattle, pigs and poultry.

c) Sheep were known to be affected commonly with a TSE, namely scrapie, which was endemic in GB flocks. Sheep offal had been incorporated into MBM for feeding to cattle at least since the beginning of the century, and in increasing amounts since the 1940s. From around 1980 there had been an increase in the sheep population in Britain, and a probable increase in the number of scrapie-affected flocks. A further suggestion was that there had been a greater inclusion of sheep heads and condemned sheep in rendering material.

d) Continuous rendering processes were gradually introduced to replace batch rendering during the late 1970s and early 1980s. There was also a marked decline in the use of hydrocarbon solvent extraction of fat from MBM, which coincided in time with the estimated date of exposure of the cattle population.⁽²⁾ It was postulated that these changes might have led to failure to inactivate, or reduced inactivation of, the scrapie agent.

e) The simultaneous occurrence of cases in herds throughout England in 1987-88 suggested that this was an extended common source epidemic with every case representing an index case. This indicated that on each occasion the infection had crossed the species barrier from sheep to cattle. Modelling suggested that the exposure of the cattle population commenced in the winter of 1981/1982. No single feed compounder was common to all affected herds.

Evaluation of these assumptions
The first two of these assumptions, namely that BSE was a transmissible spongiform encephalopathy and that the vector for the causative agent was MBM, will not be examined at the hearing. At the hearing the Committee wish to explore the basis for the remaining assumptions, and in particular the assumption that the epidemic was an extended common source epidemic, which it seems to the Committee was the foundation for the conclusions reached.

Extended common source epidemic
The Committee would like to explore whether it is right to conclude that the first cases of BSE identified were necessarily index cases from an extended common source, or whether it is possible that the epidemic had one or more point sources of infection, the recycling of which had occurred before the disease was identified, and that what was being observed in 1987 were cases resulting from that recycling.
The kuru epidemic may provide an example of a TSE epidemic arising from a point source and spreading by oral ingestion (or contamination), together with recycling through affected corpses.
If the disease had its origin in a new familial mutation of the prion gene in sheep or cattle, it could have spread through the germ-line to half the offspring of the affected carrier. Infection could have been more widespread if, for example, that carrier were a bull used for artificial insemination, producing a larger number of progeny. It has also been suggested⁽³⁾ that the use of bovine-sourced pituitary hormones (somatotrophin) might have led to transmission from an unrecognised case of BSE occurring before the start of the epidemic.
Experiments using the organophosphate pesticide, phosmet, have also raised the possibility that phosmet exposure could increase susceptibility to the BSE agent by increasing the levels of accessible PrP^c.⁽⁴⁾ This might have led to the occurrence of a small number of index cases of BSE, from which recycling then took place.
The Committee note that if BSE were the result of a localised chance infection from sheep to cattle of a mutant scrapie strain (or of a sporadic case of spongiform encephalopathy in cattle), i.e. a point source, an increasing case incidence over time would have been expected to be observed. When BSE was first identified this did not appear to be the case: the initial annual case incidence detected was of the order of one case per 100,000 adult animals, and the occurrence of BSE was geographically widespread.⁽⁵⁾
The Committee would like to discuss the possibility that there was in fact an increase in case incidence of BSE and/or in numbers of animals sub-clinically affected with BSE over time prior to its identification in 1987, but that these cases were not reported or identified as being instances of a novel disease. Identifying a new disease of this character is obviously difficult; there are several conditions that might cause animals to display symptoms similar to those associated with BSE, for example chronic hypomagnesaemia.⁽⁶⁾
Computer simulation modelling carried out in 1988⁽⁷⁾ indicated that the values of the age specific incidences of BSE cases observed in 1987 were consistent with extended common source exposure of the cattle population having commenced in the winter of 1981/1982. However, it has also been suggested more recently that the shape of the incubation period distribution indicates that some animals were probably infected in 1979.⁽⁸⁾
The Committee would like to explore whether any other epidemic models and timescales are consistent with the epidemiological data, and to discuss which of these is most likely to be an accurate representation of the BSE epidemic.
Various mathematical and statistical techniques can be used to estimate past trends in the incidence of infection given knowledge of cases of disease over time and the distribution of the incubation period. However, such models are best constructed and applied against a thorough understanding of the underlying biology and the key epidemiological processes influencing the observed pattern. Moreover, the interpretation of trends also requires a detailed knowledge of the demography of the host population.⁽⁹⁾ In the case of BSE, it has been suggested⁽¹⁰⁾ that in order to gain insight using backcalculation it will be necessary to develop models that explicitly describe the recycling and infection processes. Ferguson and others have indicated⁽¹¹⁾ that the analysis of under-reporting in the early years of the epidemic - and its possibly artefactual role in explaining the changes seen in the age-at-onset distribution in early cohorts - begs many questions about the exact (and possibly changing) nature of the infectious agent. They suggest that the case data might therefore provide some insight into the role of passaging effects in determining the early epidemiological pattern, which is of relevance to the discussion of the Scrapie Origin Theory. In this context it is relevant to note that there would be no initial species barrier effect if the BSE agent were derived from a bovine mutation.
The Committee are interested to know whether work is in hand on the development of models that explicitly describe the processes outlined above, and, if so, on the progress made. They would like to discuss what is achievable by backcalculation, and the robustness of the results obtained. They would also like to consider the extent to which the pattern of disease observed, and the other epidemiological data, are consistent with this being a point source epidemic, and the extent to which, if at all, backcalculation can distinguish between an extended common source origin and a point source (or small number of point sources) origin for BSE.
One piece of evidence that might be of assistance in this regard is data collected on feed compounders and their supply of MBM from particular renderers. The Committee would like to explore whether such data as are available may help in pinpointing the source of contaminated cattle feed in the earliest recorded cases (in 1984 - 86) in Southern England.

Inactivation during rendering process
The next issue for consideration is the extent to which, first, the introduction of continuous rendering and, second, the decline in the use of hydrocarbon solvents for fat extraction, may have caused the BSE epidemic by virtue of decreased inactivation of the scrapie agent.

Change from batch to continuous rendering
The survey of rendering plants carried out in September and October 1988⁽¹²⁾ indicated that the timing of the change from batch to continuous rendering (first continuous plant commissioned in 1972 and other plants changed to this type of process gradually over a period of years) was not consistent with the estimated time of onset of exposure (i.e. winter 1981/1982: see para 16 above). Additionally, the results of the survey did not reveal a difference between the mean maximum temperature in the two processes, and the particle size of the raw material was found to be smaller in the continuous rendering plants, which was thought likely to enable greater heat penetration and therefore inactivation of the scrapie-like agents.
The Committee understands that for these reasons it was concluded that the change from batch to continuous rendering had not contributed to the emergence of the BSE epidemic.

Decline in use of hydrocarbon solvents for fat extraction
With regard to the theory that the effect of the decline in the use of hydrocarbon solvents for fat extraction was to remove partial deactivation steps for the scrapie agent and to allow enough infectivity to survive in MBM to cause the BSE epidemic to emerge, a number of factors call for discussion:

a) Taylor and others conducted experiments to measure the effect on the scrapie agent of 12 rendering procedures that were in use within the EU in 1991.⁽¹³⁾ Greaves were produced from scrapie-spiked raw materials and subjected experimentally to solvent extraction with hot heptane in a commercial solvent extraction plant in Scotland and then exposed to steam to drive off residual solvent. These greaves demonstrated no reduction in infectivity as a result of the treatments with hot heptane and steam. Experiments carried out by Schreuder and others⁽¹⁴⁾ using hyperbaric steam on both scrapie and BSE infected material consistently indicated that the BSE agent was more resistant to these inactivation procedures than the scrapie agent(s). Taylor also carried out laboratory-based experiments to study the effect on the BSE agent and scrapie agents of exposure to hot solvents, followed by exposure to dry heat and steam. No single process was found to be significantly more effective than any of the others, and they all produced only a slight inactivation. After exposure to hot solvents, dry heat and steam, the average loss of titre for both the scrapie (22A) and BSE (301V) strain used was only 0.8 of a log. Tissue samples were exposed to one of four solvents at a particular time and temperature combination, and also to saline for the same time and at the same temperature. The average loss of titre after treatment with hot solvent was generally comparable with that after exposure to hot saline. Samples exposed to hot solvent were then treated with dry heat and steam, and compared with samples treated with dry heat and steam only (i.e. without a hot solvent/saline step). Again the average loss of titre was generally comparable. These results suggest that it was the heat, rather than the solvents, that caused the reductions in the levels of infectivity.⁽¹⁵⁾

b) In addition the cessation of solvent extraction was not universal - in around 30% of UK rendering plants solvent extraction had never been used.⁽¹⁶⁾ It has been estimated⁽¹⁷⁾ that between 10% and 30% of meat and bonemeal produced went back to cattle. Mr Field, former president of UKRA, referred in oral evidence⁽¹⁸⁾ to the historical position in the UK, stating that during wartime the MBM produced was certainly not solvent extracted. He posed the question why scrapie had not transferred to cattle during that period before solvent extraction was widely used.

c) Northern Ireland⁽¹⁹⁾ produces approximately 60,000 tonnes of MBM annually, more than 85% by two major rendering plants. No solvent extraction has been used in either plant since before 1973 and importation of MBM from GB during the 1980's appears to have been on a limited scale. The change from batch to continuous rendering occurred in 1983-1984. On the basis that this latter change does not have an appreciable effect on infectivity, appropriate conditions in rendering plants for the emergence of BSE in Northern Ireland appear to have been present from 1973 onwards. However, the incidence of scrapie in Northern Ireland is thought to have been very low compared with that in Great Britain⁽²⁰⁾.
The Committee would like to explore the solvent extraction hypothesis. One point to consider is whether the emergence of BSE in parts of southern England earlier than its emergence in other parts of the country was coincident with any earlier abandonment of solvent extraction in those parts of the country. Another factor of possible relevance is any geographical variation in the use and reprocessing of greaves; the Committee would like to discuss the available information about this, and to consider whether there is any correlation with the geographical incidence of BSE.⁽²¹⁾ If the cessation in solvent extraction is not thought likely to have contributed to the emergence of the BSE epidemic, the Committee would also like to explore other possible explanations for the geographical variation in risk, and in particular the lower incidence of BSE in Scotland. When considering geographical variation, it would be useful to the Committee to consider the extent to which information about the natal origin of affected animals is available, and whether this can give further insights into the origin of the epidemic.

Increasing sheep population and prevalence of scrapie
A further issue for discussion is whether the increase in sheep population and in the incidence of scrapie may have contributed to the development of the BSE epidemic. A number of related factors have been suggested as providing a possible explanation for a change in the exposure of cattle to sheep-derived protein and the scrapie agent:⁽²²⁾ (a) a dramatic increase in the sheep population in Great Britain which commenced in 1980 and continued to at least 1988 (MAFF 1988); (b) a probable increase in the prevalence of scrapie-infected flocks (J. W. Wilesmith unpublished data); (c) the greater inclusion of sheep heads in material for rendering; and (d) the greater inclusion of casualty and condemned sheep in material for rendering as a result of the reduction in the number of knackers' yards.
However, in the survey of rendering plants in September and October 1988,⁽²³⁾ although not all plant owners were able to provide detailed statistics relating to changes in the type of material and the species composition since 1980, there was no evidence from the utilisable responses that either the type or species composition of the material being rendered had changed during the period 1980-1988.
It was also possible that in a rendering plant varying quantities of different materials would be rendered depending on what was happening in the area at the time. For instance, a rendering plant might receive material from an abattoir specialising in sheep during a particular month, because sheep slaughtering is seasonal.⁽²⁴⁾ It also seems likely that any increases in sheep population and scrapie incidence would have been variable both temporally and geographically.
The Committee would like to explore the likelihood that if sheep had always been a potential source of disease, cattle would have experienced the necessary degree of exposure to the scrapie agent for the emergence of BSE prior to 1981-2.

Plateau in epidemic
Although it had been suggested that a plateau in the case incidence of the disease might have been reached in 1988⁽²⁵⁾, it quickly became apparent that this was not in fact the case. This has been attributed in large part to the effect of the recycling of infected cattle into the cattle food chain via the rendering system after the initial exposure.⁽²⁶⁾
The Committee would like to discuss likely explanations for the shape of the BSE case incidence curve (both before and after correction for under-reporting and missed diagnoses).

DIFFERENCES BETWEEN THE BSE AGENT AND SCRAPIE AGENTS
The BSE agent differs in a number of features from the scrapie agent:

a) Unlike with scrapie attempts to transmit BSE to hamsters have not succeeded;⁽²⁷⁾

b) Incubation periods are shorter in mice inoculated with BSE than with scrapie;⁽²⁸⁾

c) BSE can be readily transmitted to negative line sheep, whereas scrapie cannot;⁽²⁹⁾

d) BSE was transmitted naturally in feed to exotic ungulates⁽³⁰⁾ and to exotic carnivores⁽³¹⁾ in which scrapie transmission had never occurred;

e) BSE has transmitted naturally to cats via petfood⁽³²⁾ whereas cats cannot be infected experimentally with scrapie⁽³³⁾;

f) BSE was transmitted experimentally to pigs;⁽³⁴⁾

g) Both oral and intracerebral transmission of BSE to mink produced a TSE different from scrapie in mink.⁽³⁵⁾ Oral transmission of scrapie to mink has proved difficult and is impossible with some strains;⁽³⁶⁾

h) BSE from different sources has identical incubation periods and lesion profiles on bioassay in mice indicating that only one strain of agent was involved in the epidemic whereas many different strains are known to cause scrapie;⁽³⁷⁾

i) The same brain profile as BSE was obtained by transmission of FSE and TSE in exotic species. The same signature is found in vCJD but not in sporadic or acquired CJD, nor in scrapie;⁽³⁸⁾

j) When protease-digested brain homogenates from cases of TSE are subjected to immunoelectrophoresis characteristic banding patterns are observed which are different in sporadic CJD, iatrogenic CJD, variant CJD and most strains of scrapie.⁽³⁹⁾ The pattern depends on the relative proportions of unglycosylated, low glycosylated and highly glycosylated fractions. The type 4 glycoform pattern is found in variant CJD, BSE, FSE, TSE in exotic species and BSE in experimental mice and other species;⁽⁴⁰⁾

k) BSE is even more resistant to heat-inactivation than scrapie;⁽⁴¹⁾

l) All parts of the lymphoreticular system show infectivity in scrapie, whereas only the distal ileum in cattle appears to be infective.⁽⁴²⁾
These results tend to cast doubt on the hypothesis that the cause of BSE was the scrapie agent(s).

ALTERNATE HYPOTHESES FOR THE ORIGIN OF BSE
There are alternative hypotheses for the origin of BSE, including the following:

a) The causative agent was a new mutant form of scrapie, which had crossed the species barrier to cattle.

b) The causative agent was a new bovine mutant strain for which no species barrier to cattle existed.
Neither of these hypotheses was considered likely in 1987-8 since both were inconsistent with the theory that this was an extended common source epidemic.
The Committee would like to consider these and any other alternative hypotheses.
In relation to the possibility that this was a new bovine mutant strain, the Committee is interested to know whether any animals from the first herds in which multiple cases of BSE occurred, in southern England, have been examined for bovine PrP mutations.
It is to be noted that reports from the US⁽⁴³⁾ suggested that transmissible encephalopathy in mink might be due to the feeding of so-called 'downer' cattle. One possible explanation of this is the occurrence of a sporadic case or cases of spongiform encephalopathy in cattle in the US.
One argument against the possibility of a bovine strain appears to be that the epidemic did not occur earlier than it did. An issue to be explored is whether something in particular might have triggered the epidemic at this particular stage. One possible trigger would be use of the organophosphate, phosmet, referred to above, which it has been suggested could have led to enhanced susceptibility to the disease, and sufficient numbers of cases to initiate an epidemic. Another possible explanation is that the use of bovine pituitary derived hormones from an affected animal, also referred to above, likewise led to sufficient numbers of cases to initiate an epidemic. The Committee understands that the use of bovine growth hormone began in the UK in the late 1970s, which would be consistent with the time of onset of the epidemic.
With this in mind, the Committee is interested to explore, in relation to the first herds in which multiple cases of BSE occurred in southern England, any information held by CVL about the source of cattle feed, the identification of the artificial insemination bulls used in the conception of affected animals in each farm, the use of organophosphates and the use of bovine-sourced pituitary hormones.

BABs AND MATERNAL TRANSMISSION
Certain issues arise for discussion in relation to animals born after the introduction of the ruminant feed ban, which developed BSE (BABs). The first of these is whether the cases of BABs can be entirely explained by contaminated feed.
As of 1995, more than 10,000 cases of BSE had been confirmed in animals born after July 18 1988.⁽⁴⁴⁾ A case-control study suggested that maternal transmission and transmission between animals in the herd could not account for the majority of the cases of BSE that have occurred in cattle born after the introduction of the feed ban. The maternal cohort study indicates an enhanced risk of disease in maternally 'exposed' animals of 9.6% (95% confidence limits of 5.1-14.2%).⁽⁴⁵⁾ It has been suggested that food produced before the ban was introduced, but consumed afterwards, may have been responsible for some of the BABs. It has also been suggested that ruminant feed produced after the introduction of the ban may have been inadvertently contaminated at feed mills with ingredients intended for use in feeds for other species. This theory is supported by the increase in the proportion of cases born in the eastern region of the country after the ban⁽⁴⁶⁾ which could have been because more pigs and poultry are kept in this area. The inclusion of ruminant derived protein in feed used for non-ruminants became restricted on introduction of the SBO ban in September 1990. However, it appears that there could have been a degree of non-compliance with the animal SBO ban, in which case cross-contamination after this time could have occurred.
A further issue in BABs is the extent of the role played by maternal transmission. The absence of the disease in young BABs suggests that maternal transmission occurs infrequently. The Committee would like to consider whether the data in recent years are consistent with the incubation periods one would expect to observe if animals were infected at or very close to the time of birth.

WITHIN-HERD INCIDENCEOF DISEASE
In October 1990, 78.4% of all herds affected by BSE had only one or two cases. In the following 30 months, the proportion of affected herds with only one or two cases was still as much as 59.7%. Over successive 6 monthly periods from 1988 to 1992, a 17-fold increase in the number of BSE cases per year was found to be mainly the result of an increase in the number of affected herds, rather than an increase in the within-herd incidence.⁽⁴⁷⁾ A number of factors may be related to this observation, including variations in genetic susceptibility, and the concept of low level exposure.
In relation to genetic susceptibility, the low average within-herd incidence could be explained if clinical cases of BSE occurred only in cattle of an uncommon genotype, which rendered them particularly susceptible. Investigations of the results of the long-term cohort study of maternal transmission have indicated that genetic predisposition might play a role in the enhanced risk of developing BSE observed in calves born to BSE-infected dams.⁽⁴⁸⁾ Other analyses have not provided statistically significant evidence for the inheritance of susceptibility to the disease.⁽⁴⁹⁾ Susceptibility to infection with BSE might also be enhanced, for example, by the presence of a gastro-intestinal infection.
Another possible explanation for the low average within-herd incidence is that the average exposure to infection in feed was at a very low level, analogous to a limiting dose, such that cases occurred infrequently and unpredictably.⁽⁵⁰⁾ The Committee understands this to mean that the amount of infectivity in feed was at the threshold of what might be termed an effective dose, so that only a small number of animals (perhaps those that were slightly more susceptible) succumbed to the disease. It has also been suggested that infectivity might not be uniformly distributed in feed, but rather might be found in 'packets' of infection, which would account for only those animals that ate an infected 'packet' succumbing to disease.
The Committee would like to discuss the implications and possible explanations of the low average within-herd incidence of BSE in affected herds.
The Committee would also like to discuss variations in susceptibility according to age, and to explore whether any conclusions can be drawn as to the age of greatest susceptibility and the implications of this.

1.

¹ YB96/1.22/1.1-1.4

2.

² Solvent extraction was still used in two rendering plants, both in Scotland, where there was a very low incidence of BSE: Wilesmith, J., Ryan, J. and Atkinson, M. (1991) Bovine Spongiform Encephalopathy: Epidemiological Studies on the Origin. Veterinary Record. 128, 199-203. (J/VR/123/199).

3.

³ S Maddocks 1 and 2 (WS 467 and 467A).

4.

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5.

⁵ Wilesmith, J., (1991) Epidemiology of bovine spongiform encephalopathy Seminars in Virology 2: 239

6.

⁶ Mr Eddy T 62 page 69, 84.

7.

⁷ Wilesmith, J., Wells, G., Cranwell, M. and Ryan, J. (1988) Bovine Spongiform Encephalopathy: Epidemiological Studies. Veterinary Record. 123, 638. (J/VR/123/638).

8.

⁸ Professor Anderson T 4 p12 line 22.

9.

⁹ Donnelly, C., Ferguson, N., Ghani, A., Woolhouse, M., Watt, C. and Anderson, R. (1997) The epidemiology of BSE in cattle herds in Great Britain I: Epidemiological processes, demography of cattle and approaches to control by culling. Philosophical Transactions of the Royal Society of London Series B. 352, 781. (J/PTRS/352/781).

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¹⁰ Ferguson, N., Donnelly, C., Woolhouse, The Epidemic of BSE in Cattle Herds in Great Britain. II. Model Construction and Analysis of Transmission Dynamics. Philosophical Transactions of the Royal Society of London Series B. 352, 803. (J/PTRS/352/803).

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¹¹ Ferguson, N., Donnelly, C., Woolhouse, The Epidemic of BSE in Cattle Herds in Great Britain. II. Model Construction and Analysis of Transmission Dynamics. Philosophical Transactions of the Royal Society of London Series B. 352, 803. (J/PTRS/352/803).

12.

¹² Wilesmith, J., Ryan, J. and Atkinson, M. (1991) Bovine Spongiform Encephalopathy: Epidemiological Studies on the Origin. Veterinary Record. 128, 199-203. (J/VR/123/199).

13.

¹³ Taylor, D., Fernie, K., McConnell, I., Ferguson, C. and Steele, P. (1998) Solvent extraction as an adjunct to rendering: the effect on BSE and scrapie agents of hot solvents followed by dry heat and steam. Veterinary Record. 143, 6-9. (J/VR/143/6).

14.

¹⁴ Schreuder, B., Geetsma, R., Van Keulen, L., Van Asten, J., Enthoven, P., Oberthur, R., De Koeijer, A. and Osterhaus, A. (1998) Studies on the efficacy of hyperbaric rendering procedures in inactivating bovine spongiform encephalopathy (BSE) and scrapie agents. Veterinary Record. 142, 474. (J/VR/142/474).

15.

¹⁵ Taylor, D., Fernie, K., McConnell, I., Ferguson, C. and Steele, P. (1998) Solvent extraction as an adjunct to rendering: the effect on BSE and scrapie agents of hot solvents followed by dry heat and steam. Veterinary Record. 143, 6-9. (J/VR/143/6).

16.

¹⁶ Wilesmith. J., Ryan, J. and Atkinson, M. (1991) Bovine Spongiform Encephalopathy: Epidemiological Studies on the Origin. Veterinary Record. 128, 199. (J/VR/128/199).

17.

¹⁷ T 52 Wilesmith p 67.

18.

¹⁸ T 60 p 29.

19.

¹⁹ Denny, G. and Hueston, W. (1997) Epidemiology of Bovine Spongiform Encephalopathy in Northern Ireland 1988 to 1995. Veterinary Record. 140, 302. (J/VR/140/302).

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21.

²¹ Wilesmith. J., Ryan, J. and Atkinson, M. (1991) Bovine Spongiform Encephalopathy: Epidemiological Studies on the Origin. Veterinary Record. 128, 199. (J/VR/128/199).

22.

²² Wilesmith, J., Wells, G., Cranwell, M. and Ryan, J. (1988) Bovine Spongiform Encephalopathy: Epidemiological Studies. Veterinary Record. 123, 638. (J/VR/123/638).

23.

²³ Wilesmith, J., Ryan, J. and Atkinson, M. (1991) Bovine Spongiform Encephalopathy: Epidemiological Studies on the Origin. Veterinary Record. 128, 199. (J/VR/128/199).

24.

²⁴ T 60 Foxcroft p 31.

25.

²⁵ Report of the Working Party on Bovine Spongiform Encephalopathy (Southwood Report) February 1989 (IBD 1 Tab 2).

26.

²⁶ Wilesmith, J., and Wells, G., (1991) Bovine Spongiform Encephalopathy from Chesebrough (Ed) "Transmissible Spongiform Encephalopathies: Scrapie, BSE and Related Human Disorders" 59.

27.

²⁷ Kimberlin & Walker (1977) Characteristics of a Short Incubation Model of Scrapie in the Golden Hamster. Journal of General Virology, 34, 295-304. (J/GV/34/295); YB88/7.18/4.1.

28.

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29.

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30.

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