NR ASMV
AU Matthews,D.
TI Sourcing Considerations for Cattle Material
QU Workshop on TSE Risks in Relation to Source Material, Processing, and End-Product Use. June 8-9, 1998, College Park, MD
IA http://www.life.umd.edu/jifsan/tse/program.htm
PT Workshop
AB Policy on all aspects BSE has necessarily evolved by extrapolation from available evidence from scrapie of sheep and goats, as well as laboratory models of the disease. With time our understanding of BSE has enabled policy to be modified, but perhaps not to the full extent that rational risk assessment might justify. The global nature of trade in ruminants and their by-products highlights the need for rational determination of risk, associated with greater guarantees of traceability of both primary and secondary products. Traceability, coupled with a developing capacity to carry out surveillance for TSE infection, must be seen to represent opportunities rather than burdens on industry and national administrations. The consequences to the farmer, country or intermediate processors must be considered with great care if they are not to represent disincentives to the open disclosure of the presence of disease.
VT
As Will Hueston has rightly said, in deciding to attend this Conference I did carry out some form of risk analysis but, as is usually the case with TSEs, I was rather short of the necessary data. I was not aware, for example, that I was going to have to stand in for John Wilesmith, who has unfortunately had to give his full attention to our Public Inquiry on BSE. So what you will get is a rather hurriedly prepared talk and I apologise if it appears a little unscripted. It is very much a personal view, not necessarily that of the UK Government, and based upon my experiences particularly in the drafting of European standards for the sourcing of tissues for use in medical devices.
In those discussions we had very rational consideration of real risks or risks that were assumed because they were extrapolated from sheep scrapie. Then, at a very late stage in drafting, the inclusion of one or two new participants changed the perspective entirely and centred particularly on perceived risks. Even the importation of cattle from a country with no BSE into the UK on the day of slaughter, for slaughter under supervision with total guarantees of separation from UK cattle and products, suddenly represented an unacceptable risk. Even worse, even if that importation had been into the Netherlands where there have only been two cases of BSE that was seen to represent an unacceptable risk. To my mind something had gone seriously wrong between the extrapolation on the scientific basis from scrapie to the more instinctive perceived risk approach where suddenly everything was seen to be dangerous.
I do not personally believe that any country in the world can claim to present zero risk with respect to TSEs whether it be from humans or from animals, whether you believe in the prion theory or a viral origin for TSEs. So effectively what I am looking for is a risk reduction, and it is possible to make significant reductions in risk by the simple elimination of the use of certain tissues. It is, however, particularly important to get over the message that zero risk is not attainable and that risk reduction processes with respect to TSEs can conceivably increase risks from other causes as a consequence of the action taken. Unfortunately Governments are not particularly good at handling perceived risks and at getting these messages across; neither are scientists, especially those armed with no data, or at most very little data. The best we can do is to make use of our research to inform the debate and, hopefully, to actually take advantage of any new data that comes forward. Failure to do so inevitably renders that research worthless. We must accept, however, that we can never prove the negative and that hypotheses do not become fact until proven. The term prion is used so freely these days that many, including Ministers and officials, do not fully appreciate how much we still have to learn about the TSEs in general and their causal agents. Certainly the popular press tend to throw the terminology around as if everything was known and the lay audience can become quite horrified when they realise how little data is available upon which to base policy. That does not actually prevent us from taking action as is highlighted by the decline in the UK epidemic but whatever action is necessary in any country should be proportionate to the estimated risk bearing in mind that risk reduction with respect to TSEs could generate a larger alternative risk, for example through the withdrawal of certain tissues or products from general use. The 1997 SRM proposals in Europe, for example, which inevitably had a knock-on effect around the world, suddenly left us with the prospect of having to withdraw medication from the shelf for several months before they could be replenished. The medical world realised that the risk was probably greater than that actually presented by using existing stocks. We all have to accept that Governments instinctively find it easier to protect against external risk than to protect against perceived internal risk. All Governments are, after all, subject to the normal democratic process in their own countries.
Now turning to cattle as a source material the factors that have to be considered, as outlined by Stuart MacDiarmid, involve the source tissue, breed, genotype and age. Contrary to the evidence with sheep, there is currently no strong evidence in favour of attempting to use genotype to identify or eliminate risk with respect to BSE. While for some time it was believed that there was no genetic involvement in determining susceptibility to BSE, the cohort study results published in 1996 did suggest that there was an involvement, although slight. At the moment, however, the science is not well enough advanced to be able to use it in selecting tissues.
In selecting sources, herd management issues have to be taken into account but, when talking about trade in commodities world-wide, importing countries inevitably seek guarantees. It is very difficult for central authorities to provide guarantees down to farm level audits on every farm. There is a move to increase the extent of traceability of animals, especially in the UK, possibly extending to tracing of the commodity whether it be a primary or secondary product. Another factor in actually providing additional guarantees is of course surveillance which will be addressed later.
In considering the bovine tissues and starting with tissues from naturally infected and clinically affected cattle, we have only found infectivity so far in the brain, spinal cord and retina. In over 40 other tissues we have not found infectivity, although, we accept that that does not prove that there is no infectivity present at all. It does, however, suggest that, if present, infectivity is present at low titre only. I supplement that statement by telling you that in an experiment which involves intracerebral challenge of cattle with either spleen or pooled lymph node taken from clinically affected cattle the challenged cattle are now still healthy 65 months post-exposure. Inoculation with brain tissue would kill them or at least precipitate onset of clinical signs as early as 500 days post-inoculation. At the very least the spleen and lymph node challenge, both tissues in which we expected to find infectivity, is indicating that titres of infectivity in them are massively lower than in the brain.
Now turning to the experimental challenges, we can start to address the age related risks. I refer here particularly to the pathogenesis experiment where results were published in the Veterinary Record in January. For those who are not aware of the experiment, it involves an oral challenge with 100g of homogenised bovine brain at four months of age. Cattle were then sequentially killed at roughly four monthly intervals and tissues from those cattle were pooled and inoculated into mice for bioassay. Inevitably this experiment has taken a long time and is still incomplete. The last bovine challenge group was killed 40 months post-inoculation, when clinically affected. One has then to add another 900 days for the last mouse bioassay to fully appreciate the length of this experiment. There have been 11 sequential kills in the experiment and mouse assay of tissues from 10 of those kills are complete as of last month. So the results reported here are right up-to-date and not yet fully published. The final assay, from the eleventh kill, will be completed in December 1998. So far we have found infectivity in the distal ileum between 6 and 18 months after exposure, apparently with increasing titres as indicated by shortening incubation periods in mice. The ileum was again positive from 36 months onwards at a time when the animals were clinically affected. Clinical onset started in this experiment at about 35 months post-challenge which is earlier than would have been expected for the majority of naturally infected cattle. This may simply reflect the relatively large dose used in this experiment. It is particularly interesting that no infectivity was found in the distal ileum between 22 and 32 months and even subsequent to that titres appeared to be low. I should stress that there have been no titrations of infectivity in this experiment so far. References to titre are based solely on hit rates and incubation periods in mice.
Caudal medulla and spinal cord were positive from 32 months post-challenge to the end of the experiment at 40 months pi. Similarly, dorsal root and trigeminal ganglia were also positive from 32 months pi. The only new result to report here is that trigeminal ganglia were positive at 40 months pi. So, effectively we have only seen infectivity in CNS tissue or in closely allied ganglia, together with distal ileum where we had in fact expected to find it based upon the pathogenesis of scrapie. There is one other interesting result, currently uninterpretable, and that is a positive assay for bone marrow at 38 months post-inoculation. Should we find infectivity at 40 months pi it may assist interpretation of this particular result. At present, cross-contamination cannot be ruled out as a possible cause of this positive assay. A paper has been submitted for publication in the Veterinary Record with the additional bone marrow results but the Journal has recommended that publication be delayed to enable the results of the assays for kill 10 to be included. This is the assay that has recently been completed. This paper will debate the significance of this bone marrow result.
One might hope that when spending such large amounts of money on research into BSE that, at some point, it actually informs the debate on risks, certainly with respect to risks associated with cattle. Hopefully that can actually precede total elimination of BSE from any country. It has to be remembered that although BSE is seen as being widespread in the UK, 63% of herds have still never had a case. Many of those herds will not have been fed ruminant protein and because of management practices, by all rational assessments, they have to be considered un-exposed. I refer particularly to herds in the beef suckler sector where cows do not routinely receive dietary supplements, or possibly herds established by pharmaceutical companies or medical device companies solely to provide tissues for their own products. The real difficulty here for any country is in providing all the necessary guarantees with respect to historical feeding practices and potential exposure, particularly in the absence of a live animal diagnostic test. The absence of central control all the way down to farm level precludes access to such data. The cost of introducing such measures is obviously substantial and would be resisted by many countries. Even in the UK there has been a reluctance to incur some of these costs, but now we are reaching the point where from September 1998 there will be a database that will record all movements of bovines in the country. Even at this stage, however, despite the massive costs to the UK of the epidemic and the consequences of 1996 and onwards, there is still a debate as to whether data on animal movements should be gathered retrospectively. Simplistically, one might seek to put onto the database only the details of animals born from the point at which the database goes live, but it could then be argued that there would need to be a period of several years before there was sufficient data held to enable authoritative guarantees to be given. The entry of retrospective data would help but would inevitably be challenged if systems do not exist for thorough validation of the data. Such issues represent major problems that still need to be resolved in any country, but it is frustrating how few people identify marketing opportunities when most perceive obstacles only. I refer here not only to systems of traceability but also to methods of marketing meat and meat products. Can a meat product be produced that guarantees to the purchaser that it represents no risk, certainly with respect to TSEs? Industries have tended to want to retain existing practices while they waited for the "BSE problem" to go away. I honestly believe that there are now lessons to be learned and opportunities to be grasped in these situations.
That applies equally to surveillance which should not be seen solely as a burden on Government or on consumers or industries. While the application of post-mortem tests to animals slaughtered for human consumption may be criticised it has to be remembered that they may only be partially inadequate rather than totally unusable. They may for example not be able to confirm that the animal is uninfected but if the pathogenesis of BSE suggests that the prime risks are associated with CNS and, possibly, distal ileum would there not be a massive reduction in risk if one eliminated from the food chain animals, or certain tissues from them, if the CNS was shown to be PrPBSE positive? If tests could be applied to the distal ileum then the same could apply possibly at an earlier stage in pathogenesis. No test that is PrP based will be perfect but one can reduce risk by targeting animals that are positive and simply eliminating those from a production chain. If such measures were introduced to reassure consumers they would also represent opportunities in carrying out surveillance. They could support statements of freedom from any country that has not got BSE or scrapie or facilitate eradication where there is disease, as well as allaying consumer fears. It is, however, still essential to recognise that even with the use of such tests some risk will always remain.
Once again, however, action in the form or surveillance programmes has to be proportional to the estimated risk. One might expect New Zealand to have to do far less in surveillance terms to prove its freedom from BSE than perhaps the UK which would start from a point of high incidence. Draconian consequences will inevitably prove to be a disincentive to meaningful surveillance, whether it be the total loss of an internal meat market following the first identification of a PrP positive bovine at slaughter or whether it is the closure of an export market following that first diagnosis. At what point does total herd slaughter become a disincentive to a farmer to actually report disease to central authorities? While one might argue that with cattle it will be very difficult to conceal infected animals, or at least clinically affected animals, this may not be true of scrapie. I would also hope that any introduction of improved surveillance programmes in all countries would actually help to inform the debate on risks and the means by which risks could be reduced. While accepting that there are limitations to any diagnostic tests that may be used, providing that they do not produce an unacceptable number of false positive results, the identification and elimination of positive animals/carcases has to represent a transparent risk reduction strategy. It may even go so far as to tell us whether or not there are indeed any TSE free countries.
AD Dr. Danny Matthews, Ministry of Agriculture, Fisheries and Foods, Surbiton, Surrey, United Kingdom
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SP englisch